6alpha-fluoro-16-methyl - 4 - pregnene 3,20-diones and intermediates produced in the synthesis thereof

ABSTRACT

THIS INVENTION RELATES TO CERTAIN NOVEL STEROIDS, MNORE PARTICULARLY TO 6A-FLUORO-11B,17A, 21-TRIHYDROXY-16-METHYL4-PREGNENE-3,20-DIONE, 6A-FLUORO-17A,21-DIHYDROXY-16 METHYL-4-PREGNENE-3,11,20-TIONE, 6A-FLUORO-11B,17A,21TRIHYDROXY - 16 - METHYL - 1,4 - PREGNADIENE -3,20 - DIONE, 6A-FLUORO-17A, 21-DIHYDROXY - 16 - METHYL - 1,4 PREGNADIENE-3,11, 20-TRIONE, THE 9A-HALO, ESPECIALLY THE 9AFLUORO, COMPOUNDS CORRESPONDING OTHER WISE THERETO, 21ESTERS EACH, THE CORRESPONDING 21-FLUORO AND 21-DESOXY COMPOUNDS, AND INTERMEDIATES IN THE PRODUCTION THEREOF.

United States PatentOffice Patented Jan. 19, 1971 3,557,1586a-FLUOR0-16-METHYL 4 PREGNENE 3,20-

DIONES AND INTERMEDIATES PRODUCED [N THE SYNTHESIS THEREOF Frank H.Lincoln, Kalamazoo, William P. Schneider, Kalamazoo Township, KalamazooCounty, and George B. Spero, Kalamazoo, Mich., assignors to The UpjohnCompany, Kalamazoo, Mich., a corporation of Michigan ll No Drawing.Continuation-impart of applications Ser. No. 753,157, Aug. 4, 1958, andSer. No. 800,090,

Mar. 18, 1959. This application Jan. 22, 1962, Ser. 1N0.

Int. Cl. C07c 169/32 US. 01. 260397.45 28 Claims ABSTRACT OF THEDISCLOSURE This invention relates to certain novel steroids, moreparticularly to 6a-fluoro-11fi,17u,21-trihydroxy-16-rnethyl-4-pregnene-3,20-dione, 6a fluoro 1701,21 dihydroxy-IG- methyl 4pregnene-3,11,20-trione, 6oc-flI101O-1 1;3,17oz,21- trihydroxy 16 methyl1,4 pregnadiene 3,20 dione, 60c fluoro 1701,21 dihydroxy 16 methyl 1,4

5 pregnadiene-3,11,20-trione, the 9a-halo, especially the 91xfluoro,compounds corresponding otherwise thereto, 21- esters of each, thecorresponding 21-fluoro and 21-desoxy compounds, and intermediates inthe production thereof.

This application is a continuation-in-part of application Ser. No.753,157, filed Aug. 4, 1958, and Ser. No. 800,090, 15 filed Mar. 18,1959, now abandoned.-

The novel compounds of this invention and a process for their productioncan be illustrated by the following formulae:

XXII

XXIII XXIV wherein R is lower-alkyl, i.e., containing from one to eightcarbon atoms, inclusive, preferably methyl or ethyl, R is hydrogen orlower-alkyl, preferably hydrogen, R" is an aryl or alkyl sulfonylradical preferably that of a hydrocarbon sulfonic acid containing fromone to twelve carbon atoms, inclusive, e.-g., lower-alkyl, methyl, aryl,phenyl, p-tolyl, sym.-xylyl-sulfonic acid, n is an integer from one totwo. Ac is the acyl radical of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive, X is a halogen having anatomic weight from to 127, inclusive, i.e., chlorine, bromine or iodine,X is a halogen having an atomic weight from nineteen to 127, inclusive,i.e., fluorine, chlorine, bromine, or iodine, and X" is hydrogen,fluorine or chlorine. Lower-alkyl, Wherever it appears means containingfrom one to eight carbon atoms, inclusive, e.g., methyl, ethyl, propyl,octyl. The dotted line appearing in Formulae XI to XXIV represents a A-double bond which may or may not be present, i.e., the formulaerepresent both the A and A -compounds. The wavy line employed in theabove formulae and throughout the specification is a generic expressioninclusive of the aand B-configuration and mixtures thereof.

It is an object of this invention to provide the 160:- epimers andl6fl-epimers, as well as mixtures of the 160:- and 16,B-epimers of thefollowing novel compounds: 6afiuoro 1113,171,2l-trihydroxy-16-methyl-4-pregnene-3,20- dione and 21-esters thereof,6a,9a-difiuoro-11fl,17a,21-trif z-F H3 on XXIhydroxy-l6-methyl-4-pregnene-3,20-dione, esters thereof and the9a-bromo, 9a-i0d0 and 9oc-Chl010 analogues there of that areintermediates in the production of the 9u-fiuoro compound, as well asthe 9(11)-dehydro and 9fl,11fi-epoxy intermediates in the production ofthe 9a-fluoro compound, 6a-fiuoro-16-methyl-17a,21-dihydroxy-4-pregnene-3,11,20trione and 2l-esters thereof, 6a,9a-difiuoro-16- methyl17a,21-dihydroxy-4-pregnene-3,11,2-0-trione and 21-esters thereof, aswell as the 9a-chlor0, 9a-bromo and 9a-i0d0 analogues thereof,6a-fluoro-115,17a-dihydroxy- 16 methyl 4pregnene-3,20-dione,6a-flu0lO-9a-Chl010- and ,9udifluoro-l15,17a-dihydroxy-16-methyl-4-preg- 60 nene-3,20-dione andintermediates in the production there- 3,20-dione, 55,21 difluoro 90cchloro and 65 9.131-

trifiuoro 115,170 dihydroxy-16-methyl-4-pregnene-3,20- dione, andintermediates in the production thereof, 60;,21- difluoro 16 methyl17a-hydroxy-4-pregnene-3,11,20- trione, 605,21 difluoro 9a chloroand6a,9a,21-trifluoro 16 methyl l7a-hydroxy-4-pregnene-3,11,20- trione andintermediates in the production of the above compounds, and the A-analogues of each of the above compounds. It is another object toprovide processes for the production thereof and pharmaceuticalpreparations and mixtures thereof. Other objects will be apparent tothose skilled in the art to which this invention pertains.

The novel compounds of this invention, especially the 16ozand16,8-epimers and mixtures thereof of 6a-fiuoro- 118,17a,2l-trihydroxy-16-methyl-4-pregnene 3,20-dione, 6a-fluoro-16-methyl1711,21 dihydroxy 4 pregnene- 3,11,20-trione, 6a-fiuoro 11,8,l7u,21trihydroxy 16- methyl-1,4-pregnadiene-3,20-dione, 6a-flnoro-16-methyll7ez,2l-dihydroxy-1,4-pregnadiene-3,l1,20-trione, 604,90:-difluoro-l1B,17a,21-trihydroxy-16-methyl 4 pregnene- 3,20-dione,6a,9u-difluoro-16-methyl-l7u,2l-dihydroxy-4- pregnene-3,l1,20-trione,606,90: difluoro-11B,17a,21 trihydroxy-16 methyl1,4-pregnadiene-3,ZO-dione, 60:,904- difiuoro-16-methyl-l7a,21dihydroxy-1,4 pregnadiene- 3,11,20-trione and their 21-esters as definedhereinabove, and the 2l-desoxy-21-fluoro and 21-desoxy analoguesthereof, are highly active anti-inflammatory agents with improved ratioof therapeutic activity to undesirable sideeffects, e.g.,gastrointestinal disturbances, salt retention, edema, etc., known toexist with similar know physiologically active steroids. Many of thehigher molecular weight esters, particularly the ones resistant tohydrolysis and/ or more insoluble in body fluids, provide compounds withprolonged activity over the corresponding 21-hydroxy compounds. Thecompounds named above are useful in the treatment of variousinflammatory conditions of the skin, eyes, respiratory tract and thebones and internal organs due to bacterial or viral infections, contactdermatitis and allergic reactions, rheumatoid arthritis, and possessimproved therapeutic ratios of anti-inflammatory activity to undesirableside-effects, compared to the corresponding compounds without the methylgroup. For this purpose they may be incorporated in the various inertointments, cremes, lotions and sprays well known in the art. They may becombined with the known antibiotics, especially the penicillins,neomycin, tetracycline, chloromycetin and novobiocin. The 9oc-Ch1010compounds of the present invention, while somewhat less active asantiinflammatory agents than the corresponding 9a-fluoro compounds,often have a better therapeutic ratio of antiinflammatory activity toundesirable side-effects, e.g., catabolic activity.

Other of the compounds of the present invention, as well as being usefulas intermediates in the production of the above-described compounds alsopossess useful physiological activity, including glucocorticoid,mineralocorticoid and anti-inflammatory activity. Notable among theseare compounds XIII, XIV and XV, and the corresponding 21-hydroxycompounds.

The novel compounds of the present invention are prepared from3,1I-diketo-16u-methyl-4,17(20)-[cis]- pregnadien-21-oic acidlower-alkyl ester (I) by the following reactions: While the followingdescription relates to the preparation of the 16u-methyl compounds ofthe invention it is to be understood that the corresponding 16,8-methylcompounds of the invention can be obtained by exactly the same series ofreactions employing the 16,9-epimer of the starting material (I). Inlike manner by employing as starting material a mixture of the 16ocand16/3-epimers of (-I) there can be obtained a mixture of the 16mandIGfi-epimers of the various compounds of the invention which mixturescan, if desired, be separated into their components at any particularstage of the synthesis by conventional procedures, such as fractionalcrystallization, chromatography, counter-current distribution, and thelike, or any combination thereof.

The 3-keto group of the 16a-epimer of (I) is ketalized according to themethod of U.S. Pat. 2,707,184 or 2,758,993 to produce the 3-ketal of3,11-diketo-16amethyl-4,17(20)-[cis]-pregnadien-2l-oic acid lower-alkylester (II). Ethylene glycol is the preferred ketalizing agent and themethyl and ethyl esters are preferred.

The next step of the process of this invention involves the epoxidationof the (6)-double bond of a 3-ketal of 3,11-diketo 16a methyl-4,17(20)-[cis]-pregnadien 21- oic acid lower-alkyl ester with a peracid, e.g.,peracetic or perbenzoic, or other known epoxidizing agents, to producethe corresponding 5,6-epoxide (III). A mixture of 'both the aandfl-e'poxides is produced in this epoxidation reaction, and the mixturecan be separated by chromatographic or crystallization techniques knownin the art. The OL-BpOXide is employed in the next step.

The next step is an epoxide opening step in which a 3-ketalized3,11-diketo-5u,6a-epoxy-16a-methyl-17(20)- [cisJ-allopregnen-Zl-oic acidlower-alkyl ester (III), is reacted with hydrogen fluoride, to open theoxide ring and produce the corresponding 3-ketalized 3,11-diketo-5ot-hydroxy-6/3-fluoro 16oz methyl 17(20)-[cis]-al1opregnen-Zl-oic acidlower-al-kyl ester (V). This epoxide opening step is ordinarily carriedout at temperatures between about minus forty and plus fifty degreescentigrade, the preferred limits being between about zero and 25 degreescentigrade. It can be performed under anhydrous conditions in thepresence or absence of a catalyst, e.g., boron trifiuoride, or underaqueous conditions in which case the ketal group is removed byhydrolysis. Reaction conditions, e.g., those disclosed by Schmidlin etal., Helv. Chim. Acta, 36, 1241 (1953); Gallagher, J. Biol. Chem. 162,495 (1946); Cornforth et al., J. Chem. Soc., 1954, 907 and Fried et al.,J. Am. Chem. Soc., 75, 2273 (1953), are usually employed. As anhydrousconditions are often difficult or inconvenient to maintain, the oxideopening reaction is preferably performed under aqueous conditions inwhich case the ketal group will be hydrolyzed at the same time toproduce IV. The thus-produced 3-keto group of IV can then be reketalizedin the manner described hereinabove to produce the corresponding ketal(V).

The next step of the process of the present invention is a reductionstep in which a 3-ketalized 3-keto-5a-hy droxy 6Bfluoro-l6a-methyl-l7(20)-[cisl-allopregnen 21-oic acid lower-alkyl ester(V), preferably the 3-ethylene glycol ketal of 3,11-diketo 5ahydroxy-618-fluorol6a-methyl-17(20)-[cis] allopregnen 21 oic acidlower-alkyl, preferably methyl or ethyl, ester, is reduced with lithiumaluminum hydride or other chemical car- 'boxyl reducing agent in anorganic solvent, e.g., ether, dioxane, tetrahydrofuran, benzene, toproduce the corresponding 3-ketalized 5a,11/3,21-trihydroxy 6B fluoro-16u methyl-17(20)-[cis]-allopregnen-3-one. At completion of thisreaction, the reaction mixture is preferably mixed with water or, anacid, an ester or carbonyl agent followed by water, to decompose anyexcess lithium aluminum hydride and organo-metal complexes. The usualreaction conditions for a lithium aluminum hydride reduction areemployed, except that a reaction temperature at room temperature orbelow is preferred, and acid, though operative and satisfactory undercarefully controlled conditions, is preferably not employed in thedecomposition step, to avoid undue hydrolysis of the ketal group.

The next step is an esterification reaction involving the conversion ofthe 2l-hydroxy group of a 3-ketal of 5a,11B,21 trihydroxy 6Bfluoro-16a-methyl-17(20)- [cisJ-allopregnen-Ii-one (VI) to a 2l-acyloxygroup so as to protect the 21-hydroxy group in the next step, i.e., theoxidative hydroxylation step. This reaction can be performed under theesterification conditions known in the art, e.g., by the reaction of IVwith the selected acid halide or acid chloride or acid bromide or theanhydride of a hydrocarbon carboxylic acid, or by reaction with theselected acid, in the presence of an esterification catalyst or with anester under ester exchange reaction conditions. Reaction conditionswhich are apt to affect the labile 3-ketal group, the 11 B-hydroxy groupor the 6-fluoro group should be avoided.

In the next step of the process of this invention, the thus-producedester (VII) is then oxidatively hydroxylated with osmium tetroxide andan oxidizing reagent, e.g.,

hydrogen peroxide, organic peracid, an amine oxide peroxide, or an aryliodo oxide, in the manner described in US. Pats. 2,769,825, 2,769,823 orin Hogg et al., J. Am. Chem. 500., 77, 4436 (1955), to produce thecorresponding 3-ketal of 5a,11 3,17a,21 tetrahydroxy 6B fluoro-16u-methylallopregnane-3,20-dione 21-acylate (VIII).

The next step of the process of this invention involves the simultaneousremoval of the 3-ketal group, the dehydration of the 5u-hydroxy groupand the epimerization of the 6,8-fluoro group of a. 3-ketal of5a,11,8,17a,21- tetrahydroxy-6fi-fluoro 16m methylallopregnane-3,20-dione ZI-acylate to produce 6a-fluoro-11,6,17u,21-trihydroxy 1611 methyl4 pregnene-3,20-dione 21-acylate (IX). Although these reactions can beperformed in sequence, i.e., removal of the 3-ketal under mildly acidicconditions, the dehydration using Girards Reagent T and theepimerization using anhydrous mineral acid, these reactions arepreferably performed simultaneously. This can be accomplished underacidic conditions, preferably employing a mineral acid in alower-alkanol, preferably methanol or ethanol, and an inert solvent forthe steroid, e.g., chloroform or methylene chloride.

The starting 3,1l-diketo 16a methyl-4,l7(20)-[cis]- pregnadien-21-oicmethyl ester is prepared from the known l1-keto-16-dehydroprogesteroneby the following reactions: The 3-keto group of ll-keto 6dehydroprogesterone is selectively protected from reaction by conversionto a 3-enamine, e.g., pyrrolidyl enamine, according to procedures wellknown in the art. The 3-enamine of 1l-keto-l6-dehydroprogesterone isthen reacted with a methyl Grignard reagent, preferably methyl magnesiumbromide or iodide, in the presence of a 1,4-addition promoting reagent,e.g., cuprous chloride, [see Grignard Reactions, Kharasch and Reinmuth,Prentice Hall, Inc., Publishers (1954), page 219, for a discussion ofother catalysts], to produce the 3 enamine of1l-keto-16amethylprogesterone. The 3-enamine group is then hydrolyzed,e.g., with aqueous alkali to produce ll-keto- 16a-methylprogresterone.

1l-keto-l6a-methylprogesterone is then converted to 3,11-diketo 16ozmethyl-4,17(20)-[cis]-pregnadien-Zloic acid lower-alkyl ester (I) in themanner described in US. Pat. 2,790,814 for the conversion of11-ketoprogesterone to 3,11-diketo 4,17(2O) pregnadien-21- oic acidmethyl ester, i.e., 1l-keto-Mot-methylprogesterone is reacted with morethan two molar equivalents each of an alkyl diester of oxalic acid,preferably methyl or ethyl oxalate, and a base, preferably sodiummethoxide'or ethoxide or potassium tertiary butoxide, to produce thealkali-metal dienolate of 2,21-dialkoxyoxalyl-1l-keto-Met-methylprogesterone. This compound, or the free enol,

e.g., prepared by reaction of the alkali-metal dienolate with aceticacid, is then trihalogenated with chlorine or bromine, preferably thelatter, to produce 2-21-dialkoxyoxalyl-2,2l,21 trihalo llketo-l6a-methyprogesterone. This compound rearranges with strong base,e.g., an alkali-metal alkoxide, in the presence of an alkanol, e.g.,sodium methoxide or ethoxide in methanol or ethanol, to produce 2-halo3,11 diketo-16a-methyl-4,17 (20)-[cis]-pregnadien-Zl-oic acid alkylester. The Z-halo group is removed by zinc and acetic acid or otherhalogen removing agent to produce 3,11-diketo 16:! methyl-4,17(20)-[cis]-pregnadien-Zl-oic acid alkyl ester (I).

The starting 3,11-diketo 16,8 methyl-4,17(20)-[cis]- pregnadien-Zl-oicacid methyl ester is prepared from the known l6fi-methylprogesterone [1.Romo et 211., E01. Inst. Quim. Univ. N. Auton. Mex., IV, 125 (1952);C.A. 9400a (1954)], by the following reactions: 16!?- methylprogesteroneis bioconverted with a species of fungus capable of introducing anlla-hydroxy group, i.e., Rhizopus arrihizus or Rhizopus nigricans, toproduce llO-hYdIOXY 16/3 methylprogesterone. This compound is oxidized,e.g., with sodium dichromate or an N-haloamide or N-haloimide to give1l-keto-l6fi-methylprogesterone.

ll-keto 166 methylprogesterone is then converted to 3,11-diketomethyl-4,17(20)-[cis]-pregnadien- 2l-oic acid lower-alkyl ester (1) inthe manner described for the conversion of1l-keto-16a-methylprogesterone to 3,11-diketo-16o-methyl 4,17(20) [cis]pregnadien- 2l-oic acid lower-alkyl ester (1) 6a fluoro 1113,17oc,21trihydroxy-16a-methyl-4-pregnene-3,20-dione (IX) or its 21-acylate (IX)preferably the 21-acetate, can be converted to numerous physiologicallyactive steroids. For example, it can be dehydrogenated in the oneposition with selenium dioxide or a fungus capable of dehydrogenating atthe one position without otherwise degrading the nucleus, e.g., of thegenus Septomyxa, to produce 6a-fluoro-11B,17a,2'1-trihydroxy-16a-methyl-1,4-pregnadiene-3,ZO-dione (X). This compound, in turn, canbe esterified to produce its 21-esters (X') according to methods knownin the art.

60c fluoro 1lfi,17oz,21 trihydroxy-16a-methyl-4-pregnene-3,20-dione21-acylate (IX) and 6oc-fi1101'O11B,17oz, 21 trihydroxy 16amethyl-1,4-pregnadiene-3,20-dione 21-acylate (X'), representedcollectively by Formula XI, can be oxidized with a N-haloamide orN-haloimide, e.g., N-bromoacetamide in pyridine or' like amine, or withchromic acid or sodium dichromate, according to methods known in theart, to produce the corresponding ll-keto compounds (XII) which, inturn, can be hydrolyzed in the manner described herein to produce thecorresponding 21-hydroxy compounds.

The 6a,9a-dihalo compounds of the present invention are prepared asfollows: dehydrating a 6oz-fit1OI0-l1fi,17oz, 21 trihydroxy 16ccmethyl-1,4-pregnadiene-3,20-dione 21-acylate or a6a-fiuoro-11,B,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dione21-acylate (XI), illustratively with sulfuric acid or preferably with anN-haloamide followed by anhydrous sulfur dioxide, produces thecorresponding 6a-fiuoro-16a-methyl-17a,21-dihydroxy-1,4,9(11)-pregnatriene-3,20-dione 21-acylate and 6CL-flll0l'0' 16a methyl170:,21 dihydroxy-4,9(11)-pregnadiene-3, 20-dione 21-acylate,respectively (XIII). Addition of a hypohalous acid, i.e., hypochlorous,hypoidous or hypobromous acid, to these latter compounds produces thecorresponding 6oc-flUOI'O-9a-halO 11B,17a,21 trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21-acylate'iand 6afluoro9a-halo-11/3,17a,21-trihydroxy-16a-methyl-4pregnene-3,20-dione21-acylate, respectively (XIV), which by treatment with a base, e.g.,anhydrous potassium acetate, yields the corresponding epoxy compounds(XV), i.e., 60 fluoro 9,8,11/3 epoxy-16a-methyl-l7a,2l-dihydroxy-1,4-pregnadiene-3,20-dione 21-acylate and 6a-fluoro-9fi,11,8-epoxy-16a-methyl-17u,21-dihydroxy 4 pregnene 3, 20-dione2l-acylate, respectively. Treatment of these epoxy compounds withhydrogen fluoride -or other hydrogen fluoride releasing agents producesthe highly active 6a,9a-difiuoro-1 1B,17a,2l-trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21-acylate and 6a,9a-difluoro-1lfl,17a,21-trihydroxy-16a-methyl-4-pregnene-3,20 dione 21-acylate,respectively (XVI). Oxidation of these latter compounds, preferably theZI-acetate, with chromicacid in acetic acid provides60,9m-dlflll01'0-l6d-mellhyl-17ot,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acylate and 6a, 9a difluoro16a-methyl-17a,21-dihydroxy-4-pregnene-3, 11,20-trione 21-acylate,respectively (XVII). Hydrolysis of the esters XVII with a base, e.g.,aqueous sodium hydroxide or sodium bicarbonate, provides the, freealcohols 6a,9a-difluoro-16a-methyl-17u,21-dihydroxy-1,4-pregnadiene-B'J1,20-trione and 6a,9a-difluoro-16a-methyll7x,21-dihydroxy-4-pregnene-3,11,20-trione. The esters of XVI aresimilarly hydrolyzed to the corresponding 21-hydroxy compounds.

The 60:,21-difl11010 compounds of the present invention are prepared bytreating 6a-fiuoro-11,8,17a,21-trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione and 6a-fiuoro-11fl,1711,21-trihydroxy-16ot-methyl-4-pregnene-3,20-dione, respectively,(XVIII) or the corresponding ll-keto compounds or their 9ot-chloro or9oz-fill0f0 analogues with an organic sulfonyl halide such asmethanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonylbromide, benzenesulfonyl chloride, naphthylenesulfonyl chloride, or thelike, to obtain the corresponding 21-sulfonate ester (XIX), e.g.,6a-fluoro-1l 8,17a,21-trihydroxy-l6amethyl-4-pregnene-3,20-dione2l-methylsulfonate or 21-ptoluenesulfonate or their 9a-chloro or9a-fluoro analogues; treating the thus-produced 21-alky1 or arylsulfonate with sodium iodide in acetone solution to obtain thecorresponding 2l-iodo compounds (XXII), e.g., Goz-fluOIO-l 15, 17adihydroxy 16a methyl-2l-iodo-1,4-pregnadiene-3, -dione and6a-fluoro-11B,17a-dihydroxy-16a-methyl-2liodo-4-pregnene-3,20-dione ortheir 9oc-flUOIO or 9a-Chl0l0 analogues; treating the thus-obtained2l-iodo compounds with silver fluoride, preferably in acetonitrilesolution to obtain the corresponding 21-fiuoro compound (XX), e.g.,6a,2l difluoro 11,8,17a-dihydroxy-16u-methyl-1,4- pregnadiene-3,20-dioneand 6a,21-difluoro-11B,17a-dihydroxy-l6u-methyl-4-pregnene-3,20-dione ortheir 9a-flll0r0 or 9a-chloro analogues; and if desired oxidizing thethus-obtained 21-fluoro compounds with chromic anhydride,N-bromoacetamide, N-bromosuccinimide, or the like, to give thecorresponding ll-keto compounds (XXI), e.g.,6a,2l-difiuoro-l6a-methyl-17a-hydroxy-1,4-pregnadiene-3,ll,20-trione and6a,2l-difiuoro-l6u-methyl-17mhydroxy-4-pregnene-3,l1,20-trione or their9u-fluoro or 9oc-Chl01'0 analogues. Alternatively, the 21-sulfonate,preferably the 21-methylsulfonate, can be treated directly withpotassium fluoride in dimethyl sulfoxide, e.g., at 100 degrees foreighteen hours or longer, to produce the 60:,21-difll101'0 compoundsdirectly. The corresponding ll-keto analogues of these compounds,prepared by oxidizing the IIB-hydroxy group of a compound represented byFormula XIX, are similarly converted from their 21-sulfonate esterdirectly to the 21-fluoro compounds.

The ZI-unsubstituted compounds of the present invention (XXIII, XIV),are prepared by treating a 21-iodo compound (XXII), e.g.,6u-fluoro-11B,17a-dihydroXy-16a-methyl-2l-iodo-1,4-pregnadiene-3,20-dione and 6afluoro 11, 3,175:dihydroxy l6ot-methyl-21-iodo-4-pregnene-3,20-dione, with a reducingagent such as sodium thiosulfate, sodium bisulfite, potassium bisulfite,or the like, in an aqueous organic solvent mixture, to obtain thecorresponding ZI-unsubstituted compound (XXHI) and if desired oxidizingthe thus-obtained 21-unsubstituted compound with chromic anhydride,N-bromoacetamide, N-bromosuccinimide, or the like, to give thecorresponding ll-keto compound (XXIV), e.g., Ga-fiIIOrO-lfiamethyl 17ahydroxy-l,4-pregnadiene-3,11,20-trione and6a-fluoro-l6rx-methyl-17a-hydroxy 4 pregnene 3,11,20- trione. The9oz-Chl010 and 9a-fluoro-21-unsubstituted compounds (XXIII, XXIV,X"-=Cl, F) are prepared by substituting the corresponding9a-halo-21-iodo compounds (XXII, X"'=Cl, F) as starting compounds in theabovedescribed reaction or converting the 9-hydrogen compounds to9u-chloro and 9a-fluoro compounds via the 9(11)-dehydro compound in themanner described hereinbefore.

The following preparations and examples are illustrative of the productsare processes of this invention, but are not to be construed aslimiting.

PREPARATION 1 11-kef0-1 6 u-methyl progesterone To a hot solution of4.56 grams (0.014 mole) of 11- keto-16-dehydroprogesterone in 45milliliters of methanol was added 2.25 milliliters of pyrrolidine withswirling. The reaction product, the 3-pyrrolidyl enamine of 11-keto-16-dehydroprogesterone, soon separated as yellowish crystals. After coolingto five degrees, the mixture was filtered, the cake washed with coldmethanol and dried under vacuum. There was obtained 4.5 6 grams of3-pyrrolidyl-3,5,l6- pregnatriene-11,20-dione melting at 154 to 169degrees centigrade.

A solution of the thus-obtained enamine in 110 milliliters oftetrahydrofuran was added slowly to a stirred suspension of 45milliliters of commercial three molar methyl magnesium bromide, 0.90gram of cuprous chloride and fifty milliliters of tetrahydrofuran. Themixture was cooled to room temperature and stirred under a nitrogenatmosphere for three hours. The excess Grignard reagent was cautiouslydestroyed by the dropwise addition of 6.5 milliliters of water. To themixture, containing 3- pyrrolidyl-16a-methyl-3,5 pregnadiene11,20-dione, was added four milliliters of acetic acid and sixteenmilliliters of methanol and the mixture was warmed until a clear darkyellow solution was obtained. Sixteen milliliters of a ten percentaqueous solution of sodium hydroxide was added, bringing the pH to 8.The mixture was heated under reflux for 45 minutes. One milliliter ofacetic acid and 250 milliliters of water were added and the cooledmixture was extracted three times with methylene chloride. The combinedextracts were washed with aqueous sodium bicarbonate solution, water andthen dried with sodium sulfate. The dried solution was evaporated andthe residue, consisting essentially of 11-keto-16a-methy1- progesterone,was dissolved in 400 milliliters of methylene chloride andchromatographed through a ZOO-gram column of magnesium silicate(Florisil). The column was developed with 400-milliliter portions ofsolvent of the following composition and order: five of hexanes(Skellysolve B) plus three percent acetone, five of hexanes plus fivepercent acetone, eight of hexanes plus seven percent acetone, five ofhexanes plus ten percent acetone, four of hexanes plus fifteen percentacetone and finally, one of acetone. Fractions 9 to 25 (counting themethylene chloride fraction) were combined and recrystallized from amixture of acetone and water to give 2.03 grams of 11-keto-16a-methylprogesterone melting at 179 to 182 degrees centigrade. Asample recrystallized from a mixture of ethyl acetate and hexanes meltedat 183 to 185 degrees centigrade, had an [04] of plus 255 degrees (CHClX213; me am 15,850

and the analysis below.

Calcd for C H 'O (percent): C, 77.15; H, 8.83. Found (percent): C,76.95; H, 8.98.

PREPARATION 2 3,11-diket0-1 6u-methyl-4J 7(20 -[cis] -pregnadien-21-0icacid methyl ester A solution of 2.00 grams (5.8 millimoles) ofll-ketol6a-methylprogesterone in thirty milliliters of dry tertiarybutyl alcohol was warmed to fifty degrees centigrade and stirred undernitrogen. To the solution was added 3.2 milliliters of ethyl oxalate and3.03 grams of a 25 percent methanolic sodium methoxide solution. Ayellowgreen precipitate of the sodium dienolate of2,2l-diethoxyoxalyl-l1-keto-16ot-methylprogesterone appeared almostimmediately.

The mixture was stirred for twenty minutes after which a cooled solutionof 0.98 gram of anhydrous sodium acetate and 0.84 milliliter of aceticacid in forty milliliters of methanol was added, thus producing the freedienol. The solution was cooled to zero degrees centigrade and thentreated dropwise with a cold solution of 2.0 grams of bromine inmethanol over a period of ten minutes. There was thus-produced2,21,21-tribromo-2,2l-diethoxyoxalyl-ll-keto-16tr-methylprogesterone Thecooling bath was removed and to the solution was added 5.72 grams of a25 percent methanolic sodium methoxide solution. The stirring wascontinued for 2.5 hours. There was thus produced2-bromo-3,1l-diketo-16amethyl-4,17(20)-[cis]-pregnadien 21 oic acidmethyl ester.

To the resulting solution was then added five milliliters of acetic acidand one gram of zinc dust and stirring was continued for thirty minutes.The mixture was diluted with water, the solids were removed byfiltration, and the filtrate extracted thoroughly with methylenechloride. The

extract was dried with sodium sulfate and evaporated. The residue wasdissolved in 400 milliliters of methylene chloride and poured over aZOO-gram column of magnesium silicate (Florisil). The column wasdeveloped with 400- milliliter portions of solvent of the followingcomposition and order: four of hexanes (Skellysolve B) plus five percentacetone, ten of hexanes plus seven percent acetone, ten of hexanes plusten percent acetone and finally, one of acetone. Fractions 14 to 23(counting the methylene chloride fraction) contained starting 11keto-16a-methylprogesterone. Fractions 7 to 12 contained3,11-dlk6tO-l6otmethyl-4,17(20)-[cis]-pregnadien-21-oic acid methylester which, when crystallized from methanol and water and then frommethanol, melted at 177 to 184 degrees centigrade, has a k213 232.5III/1., a 26,200

an [0th of plus 137 degrees (CHCl and the analysis below.

CalCd for C23H3004 (percent): C, H,

Found (percent): C, 74.58; H, 8.04.

PREPARATION 3 1 1 -ket0-1 6fi-methyl progesterone A medium was preparedcontaining ten grams of Cerelose dextrose technical grade and twentygrams of corn steep liquor (sixty percent solids) in sufficient tapwater to make up one liter of solution. One hundred liters of such amedium was adjusted by the addition of 25 percent sodium hydroxidesolution to a pH of 5. Thereto was then added 400 milliliters of lardoil and lard-oil octadecanol as an anti-foaming agent. This medium wassterilized for minutes at twenty pounds pressure and inoculated withRhizopos nigricans minus strain, American Type Culture Collection No.6227b, and incubated for 24 hours at a temperature of 28 degreescentigrade using a rate of aeration and stirring such that the oxygenuptake was 6.3 to seven millimoles per hour per milliliter of sodiumsulfite according to the method of Cooper, Femstrom and Miller, Ind.Eng. Chem. 36, 504 (1944). To this medium containing a 24-hour growth ofRhizopus nigricans minus strain was added six grams ofIGB-methylprogesterone in 150 milliliters of acetOne to provide asuspension of the steroid in the culture. After an additional 24-hourperiod of incubation under the same conditions of temperature andaeration, the beer and mycelium were extracted. The mycelium wasfiltered, washed twice each time with a volume of acetone approximatelyequal to the volume of the mycelium, and extracted twice, each time witha volume of methylene chloride approximately equal to the volume of themycelium. The acetone and methylene chloride extracts including solventswere added to the beer filtrate. The mixed extracts and beer filtratewere extracted successively with two one-half by volume portions ofmethylene chloride and then with two onefourth by volume portions ofmethylene chloride. The combined methylene chloride extracts were washedwith two one-tenth by volume portions of a two percent aqueous solutionof sodium bicarbonate and then with two one-tenth by volume portions ofwater. After drying the methylene chloride extracts with about three tofive grams of anhydrous sodium sulfate per liter of solvent andfiltering, the solvent was removed by distillation. The residue wasdissolved in a minimum of methylene chloride, filtered and the solventthen evaporated. The crude 1613- methyl-llot-hydroxyprogesterone wasoxidized directly to 16 ,B-methyl-l l-ketopro gesterone.

A solution was prepared containing 3.5 grams of the crude16fi-methy1-1lot-hydroxyprogesterone in 240 milliliters of acetic acidat room temperature; Thereto was added dropwise a solution of 0.82 gramof chromium trioxide in 82 milliliters of acetic'acid and 0.8 milliliterof water. During the addition the temperature was maintained betweentwenty to 23 degrees centigrade and thereafter for another period of oneand one=half hours. The reaction mixture was then diluted with oneliterof water and extracted with six -milliliter portions of methylenechloride. The extracts were combined, washed with dilute sodiumbicarbonate solution and water, dried overlanhydrous sodium sulfate andevaporated to dryness under reduced pressure. The thus obtainedIGB-methyl-ll-ketoprogesterone was recrystallized from methanol. I

PREPARATION 4 A solution of 2.00 grams (5.8 milliinoles) of 'll-ketol6fi-methylpro'gesterone in thirty milliliters of dry tertiary butylalcohol was warmed to fifty degrees centigrade and stirred undernitrogen. To the solution was added 3,2 milliliters ofethyl oxalate and3.03 grams of af25-percent methanolic sodium methoxide solution. Ayellow-green precipiate of the sodium dienolate of 2,2l-diethoxyoxalyl-1l-keto-16,8-methylprogesterone' appeared almost immediately.

The mixture was stirred for twenty minutesafter which a cooled solutionof 0.98 gram of anhydrous sodium acetate and 0.84 milliliter of aceticacid in forty milliliters of methanol was added, thus producingthe'free'dienol. The solution was cooled to zero degrees centigrade andthen treated dropwise with a'cold solution of'2.0 grams of bromine inmethanol over a period of ten minutes. There was thus-produced2,21,21-tribromo-2,2l-diethoxyoxalyl-l 1-keto-lfi methylprogesterone. I

The cooling bath'was removed and to the solution was added 5.72 grams ofa 25 percent methanolic sodium methoxide solution. The stirring wascontinued for 2.5 hours. There was thus produced 2-bromo-3,11*-diketo-16B-methyl-4, 17 (20) [cis] -pregnadien-21-oic acid methyl ester. i

To the resulting solution was then added five milliliters of acetic acidand one gram of zinc dust and stirring was continued for'thirtyminute's. The mixture was diluted with water, the solids wereremoved by filtration, and the filtrate extracted thoroughly withmethylene chloride. The extract was dried with sodium sulfate andevaporated. The residue was dissolved in 400 milliliters of methylenechloride and poured over a ZOO-gram column of magnesium silicate(Florisil). The column was developed with 400-milliliter portions ofsolvent of'the followingjcomposition and order: four of hexanes(Skellysolve'B) plus five-percent acetone, ten of hexanes plus sevenpercent acetone, ten of hexanes plus ten percent acetone and finally,one of acetone. Fractions 14 to 23' (counting the methylene chloridefraction) contained starting ll-keto- 16B-methylprogesterone. Fractions710 12. contained 3,11- diketo-16fl-methyl-4,1'7(20)-[cis]=pregnadien-21oic acid methyl ester.

The yield of product is increased if the initial reaction of1l-keto-l6fi-methylprogesterone with ethyl oxalate and sodiummethoxideis conducted at somewhat higher tem peratures and/ or withlonger reaction times.

Examples showing the preparationof the 16a-methyl compounds of theinvention:'

EXAMPLE 1 The 3-ethylene glycol ketal of 3,11-diketo-16u-methyl-4,17(20)-[cis]-pregnadien-2l-0ic acid methyl ester To a solution of 1.5grams of 3,11-diketo-16u-methyl 4,17(20)-[cis]-pregnadien-21-oic acidmethyl ester dissolved in 150 milliliters of benzene was added 7.5milliliters of ethylene glycol and 0.150 gram of para-toluenesulfonicacid and the whole was then heated with stirring at the refluxtemperature of the reaction mixture for 5.5 hours. The water formed inthe reaction was removed by passing the condensate through a water trap.The cooled reaction mixture was washed with 100 milliliters of a onepercent aqueous sodium bicarbonate solution. The benzene layer was thenpoured on a column of 150 grams of magnesium silicate (Florisil). Thecolumn was developed with 100-milliliter portions of solvent of thefollowing composition and order: eight portions of methylene chlorideplus four percent acetone and three portions of methylene chloride pluseight percent acetone. The methylene chloride plus four percent acetoneeluates contained the 3-ethylene glycol ketal of3,l1-diketo-16amethyl-4,17(20)-[cis]-pregnadien-2l-oic acid methyl esterwhich was freed of solvent by evaporation.

Reacting 3,11-diketo-16a-methyl 4,l7(20) [cis]- pregnadien-Zl-oic acidmethyl ester with trimethylene glycol in the presence ofpara-toluenesulfonic acid is productive of the 3-trimethylene glycolketal of 3,1l-diketo- 16a methyl-4,l7(20)-[cis]-pregnadien 21 oic acidmethyl ester.

Similarly, other 3-ketals of this and other esters of 3, ll diketo 16amethyl 4,l7(20) [cis] pregnadien- 2l-oic acid methyl ester are producedby the reaction of the selected ester of 3,11diketo-16a-methyl-4,l7(20)- [cis]-pregnadien-Zl-oic acid, e.g., methyl,ethyl, propyl, butyl, or octyl ester, with a glycol as hereinbeforedescribed, e.g., ethylene glycol, propylene glycol, trimethylene glycol,lower-alkyl substituted ethylene glycols or trimethylene glycols, in thepresence of an acid catalyst, e.g., paratoluenesulfonic acid, hydrogenchloride, sulfuric acid.

EXAMPLE 2 3-ethylene glycol ketal of3,11-diket-5u,6a-ep0xy-16amethyl-17(20)-[cis]-pregnen-21-0ic acid methylester To a solution of five grams of the 3-ethylene glycol ketal of3,11-diketo-l6u-methyl 4,l7(20) [cis]-preg nadien-21-oic acid methylester in 100 milliliters of chloroform was added a chilled solution of1.9 grams of perbenzoic acid dissolved in 31.5 milliliters ofchloroform. The solution was maintained at about four degrees centigradefor 24 hours, and then at room temperature for 72 hours. The solutionwas then washed with a five percent aqueous solution of sodiumbicarbonate and then with water. The chloroform layer was separated,dried and the solvent distilled to give a residue of the 3-ethyleneglycol ketal of 3,11-diketo 504,60 epoxy 16cc methyl-17(20)-[cis]-pregnen-2l-oic acid methyl ester.

EXAMPLE 3 3,11 -diket0-5tx-hydr0xy-6ot-flu0r0-16a-methyl-1 7 (20)allopregnen-ZI -0ic acid methyl ester To a solution of 1.73 grams of3-ethylene glycol ketal of 3,11-diketo-a,6a-epoXy-l6a methyl17(20)-[cis]- pregnen-Zl-oic acid methyl ester in sixteen milliliters ofmethylene chloride was added six milliliters of 48 percent hydrofluoricacid. The heterogeneous mixture was stirred for two hours, made slightlybasic with 300 milliliters of five percent sodium bicarbonate solution,and extracted with methylene chloride. The extract was washed, dried,and evaporated to dryness to give 1.62 grams of crude solid.Purification by chromatography over magnesium silicate gave twofractions. The first was eluted with methylene chloride plus fivepercent acetone and the second was eluted with methylene chloride plusten and twenty percent acetone. Crystallization of the first fractionfrom a mixture of acetone and Skellysolve B hexanes gave3,1l-diketo-5a-hydroxy 6B fluoro 16amethyl-17(20)-allopregnen-2l-oicacid methyl ester.

EXAMPLE 4 3-ethylene glycol ketal of 3,11 diketo 50chydroxy-Gflflu0r0-16a-methyl 17(20) [cis] allopregnen 21- oic acidmethyl ester A mixture of 1.9 grams of 68-fiuoro-3,1l-diketo-5othYClIOXY-16ot-Ill6thYl-l7(20) [cis]allopregnen-Zl-oate, 59 milligrams of para-toluenesulfonic acidmonohydrate and 31 milliliters of distilled ethylene glycol was added to800 milliliters of benzene. The mixture was stirred and refluxed for twohours, with the condensate passing through a water trap to remove thewater. Then the mixture was cooled, washed with water and evaporated todryness to give a crude solid which on recrystallization from a mixtureof acetone and hexanes gave the 3-ethylene glycol ketal of3,1l-diketo-5a-hydroxy-6B-fiuoro-16amethyl-17- (20)- [cis]-allopregnen-21-oic acid methyl ester.

Following the above procedure, substituting other dihydric alcohols forethylene glycol, for example, 1,2-propylene glycol, 2,3-butanediol,1,3-butanediol and 2,3-pentanediol, is productive of the respective3-alkylene ketals of 3,1l-diketo-5a-hydroxy-6/3-fiuoro 16oz methyl 17(20)-allopregnen-2l-oic acid methyl ester.

EXAMPLE 5 To a solution of 1.96 grams of the 3-ethyleneglycol ketal of3,11-dlkei10-5oL-hYdIOXY-GB-flLIOIO-16oL-Ill6thYl-17(20)-[cis]-allopregnen-2l-oie acid methyl ester in 850 milliliters ofanhydrous ether was added 3.7 grams of lithiumaluminum hydride. Themixture was stirred for a period of one hour, and 200 milliliters ofwater was added slowly, the ether phase separating. The aqueous phasewas extracted with ethyl acetate and the extracts added to the etherphase. The combined ether-ethyl acetate solution was washed with Water,dried and evaporated to dryness under reduced pressure. The crude solidresidue was crystallized from acetone-Skellysolve B hexanes to give the3-ethylene glycol ketal of 50:,115, 21-trihydroxy-6/3-fiuoro-16ot-methyl17(20) [cis] allopregnen-3-one.

EXAMPLE 6 The 3-ethylene glycol ketal 0] 5a,]118,21-trihydr0xy-6fifluoro16a methyl-17(20)-[cis]-all0pregnen 3 one 21 -acetate 0.87 gram of the3-ethylene ketal of 5u,ll,B,2l-trihydroxy-6/3-fiuoro-16a-methyl-l7(20)-[cis1-allopregnen 3- one was dissolved in ten milliliters of aceticanhydride and ten milliliters of pyridine. The solution was maintainedsixteen hours at room temperature and then poured into ice water to givethe 3-ethylene glycol ketal of 5a,1113,2l-tIihYdlOXY-fiB-flllOlO-16oz 5methyl 17(20)- [cis] -allopreg-nen-3-one 2 l-acetate.

Similarly, other 21-organic carboxylic acid esters of 511,115,21-trihydroxy-6;3-fiuoro-l6a-methyl-17(20) [cis] allopregnen-3-one3-ethylene ketals can be prepared wherein the 21-acyloxy group isformyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy,heptanoyloxy, octanoyloxy, benzoyloxy, phenylacetoxy, or the like, bycontacting the 3-ethylene ketal of 5u,ll,8,2l-trihydroxy-6fl-fluoro-l6a-methyl-l7(20)-[cis] allopregnen 3 one with theappropriate acylati-ng agent, e.g., the anhydride or acid halide of theselected acid in a solvent such as benzene, toluene, acetic acid, or thelike, preferably in the presence of pyridine or a similar amine.

EXAMPLE 7 The 3-ethylene glycol ketal 0f 5a,11/3,17a,21-tetrahydroxy 6Bfluoro-l6otmethylall0pregnane-3,20-di0ne 21-acetate To a solution of0.93 gram of the 3-ethylene glycol ketal of5a,l1,8-dihydroxy-6fi-fiuoro-16a-methyl 17(20)- allopregnen-3-one2l-acetate in 35 milliliters of tertiary butyl alcohol was added onemilliliter of pyridine, 2.75 milliliters of two molar Nmethylmorpholineoxide peroxide (US. 2,769,823) in tertiary butyl alcohol, and 13.1milligrams of osmium tetroxide in tertiary butyl alcohol (9.1milliliters of tertiary butyl alcohol solution containing 1.44milligrams osmium tetroxide per milliliter). The solution was stirredfor a period of eighteen hours and fifteen milliliters of five percentsodium hydrosulfite was added. Stining was continued for an additionalten minutes, at which time 0.7 gram of finely ground synthetic magnesiumsilicate was mixed into the solution fora period of twenty minutes andthen removed by filtration. The filtrate was evaporated to dryness underreduced pressure at a temperature of less than fifty degrees centigrade.The residue was dissolved in methylene chloride, washed with water,dried and evaporated to dryness. The residue was crystallized fromacetone- Skellysolve B hexanes to give the 3-ethylene glycol ketal of5u,11B,17u,2l-tetrahydroxy-6B-fiuoro 16cc methylallopregnane-3,20-dione2l-acetate.

EXAMPLE 8 A solution of 0.144 gram of the 3-ethylene glycol ketal of5a,11,8,1711,21-tetrahydroxy-6fi-fiuoro-16a methylal-1opregnane-320-dione 2l-acetate in twelve milliliters of chloroform and0.1 milliliter of absolute alcohol was cooled to minus ten degreescentigrade in an ice-salt bath and a stream of anhydrous hydrochloricacid was gently bubbled through the solution for 2.5 hours while thetemperature was maintained between minus five and minus fifteen degreescentigrade. The solution was then diluted with 25 milliliters ofchloroform, washed With dilute sodium bicarbonate and water, dried overanhydrous sodium sulfate, and evaporated to dryness under reducedpressure at sixty degrees centigrade or less to give6a-fluoro-11,8,17a,21-trihydroxy-16a-methyl- 4-pregnene-3,20-dione21-acetate.

EXAMPLE 9 A medium consisting of one percent dextrose hydrate, twopercent cornsteep liquor of sixty percent solids and tap water wasadjusted to pH 4.9 with sodium hydroxide. The medium was steamsterilized at fifteen pounds pressure for thirty minutes, cooled, andthen inoculated with a 24-hour growth, from spores, of Septomyxa afinis,A.T.C.C. 6737. The medium was agitated, and sparged with sterile air atthe rate of one-tenth volume of air per volume of medium per minute. Atthe end of 24 hours of fermentation at room temperature, the pH wasabout 7.4. To this culture there was added a solution of6a-fluoro-l1fi,17a,2l-trihydr0xy-16a methyl 4- pregnene-3,20-dione2l-acetate dissolved in a minimal amount of diethylformamide. Thesolution was prepared by dissolving five parts of the steroid in 100parts of the solvent and adding about ten cc. of the solution per literof the medium. Fermentation was continued for a period of 48 hourswhereupon the mycelium and beer were extracted thoroughly with methylenechloride. The extract was washed with sodium bicarbonate solution andthen, with water, dried and concentrated in vacuo to give6a-fiuoro-llB,17a,2l-trihydroxy-16a methyl 1,4- pregnadiene-3,20-dione.

Following the procedure of Example 9, but substituting as startingmaterial 6a-fluoro-11B,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dioneZl-acetate there was like wise produced 6a-fluoro llf3,l7a,2l trihydroxy16amethyl-1,4-pregnadicne-3,20-dione.

EXAMPLE 1O 6 oc-flllOl'O-I 15, I 7 a,21 -trihydr0xy-16mmezhyl-4-pregrtene- 3,20-di0ne A solution of 1.1 grams of6u-fiuoro-11,8,l7a,2l-trihydroxy-16a-methyl-4-pregnene-3,20-dione21-acetate, one gram of potassium bicarbonate, milliliters of methanoland fifteen milliliters of water were mixed together and purged withnitrogen to remove dissolved oxygen While stirring at 25 degreescentigrade for four hours. The solution was then neutralized by additionof acetic acid and distilled under vacuum to remove the methanol. Theresidue was extracted with 100* milliliters of methylene chloride, andthe extract was dried over sodium sulfate to give a solution of6a-fiuoro-l1,8,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dione whichwas freed of solvent by evaporation.

EXAMPLE 11 1.5 grams of 6a fluoro-l1fi,17a,21-trihydroxy16amethyl-1,4-pregnadiene-3,20-dione was dissolved in twenty millilitersof pyridine and fifteen milliliters of acetic anhydride and the mixtureheated at forty degrees centigrade for four hours. The solution wascooled and then slowly diluted with water. The precipitated steroid wasremoved by filtration, washed with water and dried to give6a-fiuoro-11,8,17a,2l-trihydroxy-16u-methyl-1,4-pregnadiene 3, 20-dione21-acetate.

6a-fiuoro-11,8,17a,21-trihydroxy 16a methyl 1,4- pregnadiene-3,20-dioneis converted to other 21-esters by reaction with the appropriate acidanhydride, acid chloride or bromide or by other methods known in theart, e.g., by ester exchange, acid in the presence of an esterificationcatalyst, etc., to produce 6a-fluoro-11fi,17a,21-trihydroxy-16a-methyl-1,4-pre-gnadiene-3,20 dione 21-acylates whichinclude those wherein the acyl radical of the 21-acylate group is theacyl radical of, for example, a lower aliphatic acid, e.g., formic,propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic,2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic,triethylacetic, heptanoic, octanoic, a-ethylisovaleric, a cyclic acid,e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, ,B-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, [i-cyclohexylpropionic, an aryl oralkaryl acid, e.g., benzoic 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic,3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic,phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (whichcan be converted to water soluble, e.g., sodium salts), e.g., succinic,glutaric, wmethylglutaric, B-methylglutaric, B,,6-dimethylglutaric,adipic, pimelic, suberic, a hydroxy acid, e.g., glycolic, lactic,citric, tartaric, d-malic, d-glyceric, mannonic, gluconic, salicylic,2,3,4-trimethoxybenzoic, a-naphthoxyacetic, or other acyl acid.

Similarly, 6a-fluoro-1 lfi,170:,2l-tlihYdIOXY-l6oc-H16ihYl-4-pregnene-3,20-dione is converted to any of the other esters named inthe paragraph following Example 11 by substituting11B,l7a,21-trihydroxy-16a-methyl 4 pregnene-3,20-dione as the startingcompound in the acylation reaction.

EXAMPLE 12 6a-flu0r0-16a-methyll 711,2I-dihydr0xy-1,4-pregrmdiene-3,11,20-lri0ne 21 -acelate To a solution of 2.5 millimoles of6aflUOrO-11B,17oc,2ltrihydroxy 16u-methyl-1,4-pregnadiene 3,20 dione 21-acetate and two milliliters of pyridine in 75 milliliters of tertiarybutanol was added 500 milligrams of N-bromoacetamide. The reactionmixture was maintained at room temperature for about sixteen hourswhereupon the solution was diluted with fifty milliliters of watercontaining 500 milligrams of sodium sulfite, and the mixture was thenconcentrated at reduced pressure to about forty milliliters. Thedistillation residue was refrigerated, filtered, and the filter cake waswashed with water and then dried. It consisted of6ot-fil10fO-16oc-1'Il6thYl-17a,21-dihydr0XY-l,4-pregnadiene-3,11,20-trione ZI-acetate.

EXAMPLE 13 Following the procedure of Example 12, but substituting6a-fluoro-1 1,8,17a,21-trihydroxy-16oz-methyl 4 pregnene-3,20-dioneZI-acetate as starting compound, there is thus produced6a-fluoro-1Got-methyl-17u,21-dihydroxy- 4-pregnene-3,11,20-trione21-acetate.

Similarly, substituting another 21-acylate of 6a-fiuoro-11B,17a,2l-trihydroxy-16a-methyl-1,4-pregnadiene 3,20- dione or21-acylate of 6a-fluoro-11B,17a,21-trihydroXy16a-methyl-4-pregnene-3,20-dione wherein the acyl radical is, e.g., thatof an acid named in the paragraph following Example 11, as the startingcompound in the oxidation reaction described in Example 12, there isthus produced the corresponding 21-acylate of6a-fluoro-16amethyl-17u,21-dihydr0xy-1,4-pregnadiene-3,l1,20 trione andof 6a-fiuoro-16a-methyl-l7a,2l-dihydroxy 4 pregnene-3,1 1,20-trione,respectively.

EXAMPLE 14 To a solution of 8.5 grams of 6a-fiuoro-11fi,17a,21-trihydroxy 16a methyl-1,4-pregnadiene-3,ZO-dione 21- acetate in 42.5milliliters of pyridine was added 5.63 grams of N-bromoacetamide. Afterstanding at room temperature for a period of fifteen minutes, thereaction solution was cooled to five to ten degrees centigrade andsulfur dioxide gas was passed over the surface of the solution whileshaking the flask until the solution gave no color with acidifiedstarch-iodide paper. During the addition of the sulfur dioxide, thereaction mixture became warm. The temperature was kept under thirtydegrees centigrade by external cooling and by varying the rate of sulfurdioxide addition. Thereafter to the reaction mixture was added 400milliliters of ice water and the resulting precipitate collected byfiltration. This material was recrystallized from acetone-Skellysolve Bhexanes to give Got-fluoro- 16a methyl17a,21-dihydroXy-1,4,9(1l)-pregnatriene- 3,20-dione ZI-acetate.

EXAMPLE 6a-flu0r0-16a-methyl-1 7a,21-dihydr0tty4,9(1 Ipregnadiene-3,20-dione 21 -acetate Following the procedure of Example14, but substituting 60c fluoro-11,3,17a,2l-trihydroxyl6a-methyl-4-pregnene-3,20-dione 21-acetate as the starting compound,there is thus produced 6a-fiuoro-16a-methyl-17a,2l-dihydroxy- 4,9 1 l-pregnadiene-3 ,20-dione 21-acetate.

Similarly, substituting another 21-acylate of 6a-fluoro- 1'1B,17u,2ltrihydroxy l6a-methyl 1,4-pregnadiene- 3,20-dione or a 21-acylate of6a-fluoro-11B,17x,21-trihydroxy-l6u-methyl-4-pregnene-3,20-dione whereinthe acyl radical is, e.g., that of an acid named in the paragraphfollowing Example 11, as the starting compound in the dehydrationreaction described in Example 11, there is thus produced thecorresponding 21-acy1ate of 6oc-flu0l0- 16a methyl17a,2'1-dihydroxy-1,4,9(11)-pregnatriene- 3,20-dione and of6a-fluoro-16a-methyl-17a,2 l-dihydroxy- 4,9 1 1)-pregnadiene-3,20-dione, respectively.

EXAMPLE 16 To a solution of 5.68 grams of 6a-fluoro-16a-methyl- 17a,21dihydroxy-1,4,9(1'1)-pregnatriene-3,20-dione 21- acetate in millilitersof methylene chloride and 250 mililiters of tertiary butyl alcohol wasadded a solution of fourteen milliliters of 72 percent perchloric acidin 100 milliliters of water followed by a solution of 2.34 grams ofN-bromoacetamide in sixty milliliters of tertiary butyl alcohol. Afterstirring the reaction mixture for fifteen minutes, a solution 'of 2.8grams of sodium sulfite in milliliters of water was added and thereaction mixture was concentrated to a volume of about 500 millilitersunder reduced pressure at about fifty degrees Centigrade. Theconcentrate was cooled in an ice bath and while stirring 500 millilitersof water was added. After stirring for a period of one hour, theprecipitated product was isolated by filtration, and the cake washedwith water and air-dried to give 6a fiuoro-9'a-bromo-l1fl,17a,21-trihydro y-16amethyl-l,4-pregnadiene-3,ZO-dione 2-1-acetate.

EXAMPLE 17 6 auoro-Qu-bromo-I 1 5,1 7a-,21-trihydr0xy-16ot-merhyl-4-pregnene-3,20-dione 21 -acetate Following the procedure of Example 16,but sulbstituting 60z-fi110l0-1Gov-IIlGlihYl-170t,21Clihyd10Xy-4,9( 11)-pregnadiene-3,20-dione 2'1-acetate as the starting compound, there isthus produced 60L-flUOI0-9ot-bI'OII10-11B;17oc,21- trihydroxy-16rx-methyl-4-pregnene-3 ,20-dione 21-acetate.

Similarly, substituting another 21-acylate of Got-fluoroa methyl17a,21-dihydroXy-l,4,9(11)-pregnatriene- 3,20-dione or a 2l-acylate of6afluoro-17o,2l-dihydroxy- 16a-methyl-4,9(1i1)-pregnadiene-3,20-dionewherein the acyl radical is, e.g., that of an acid named in theparagraph following Example 11, as the starting compound in the reactiondescribed in Example 16, there is thus produced the corresponding21-acylate of 6a-fluoro-9a-bromo- 1 15,17a21 trihydroxyl6a-methyl-1,4-pregnadiene-3,20- dione and of60t-flLlOI'O-90t-b1'OII10-11fi,170t,2)1-tIlhydIOXy-16u-methyl-4-pregnene-3,ZO-dione, respectively.

Substituting N-chlorosuccinimide for the N-bromoacetamide in thereactions described in Examples 16, 17 and the paragraph following isproductive of the corresponding 90c chloro compounds, e.g., 60c fluoro9a chloro- I'l $170521 trihydroXy-16ot-met1hyl-1,4-pregnadiene-3,20dione ZI-acetate and'6a-fluoro-9a-chloro-11B,17u,21-trihydroxy-16a-methyl-4-pregnene-3,20-dione21-acetate.

EXAMPLE 18 To a solution of 6.78 grams of 6a-fiuoro-9a-bromo 11B,17a,21trihydroxy-16a-methyl-tl,4-pregnadiene-3,20- dione 21-acetate inmilliliters of acetone was added 6.78 grams of potassium acetate and theresulting suspension was heated under reflux for a period of seventeenhours. The mixture was then concentrated to approximately sixtymilliliters volume at reduced pressure on the steam bath, diluted withwater and extracted with methylene chloride. The methylene chlorideextracts were combined, washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue was redissolved in methylenechloride and chromatographed over 500 grams of Florisil anhydrousmagnesium silicate. The column was eluted with one-liter portions ofhexanes (Skellysolve B) containing increasing proportions of acetone.There was thus eluted 6oz fluoro-913,11fl-epoxy-l6a-methyl-17a,21-dihydroxy-1,4-pregnadiene-3,20-dione21-acetate which was freed of solvent by evaporation of the eluates.

EXAMPLE 19 Following the procedure of Example 18, but substituting6tx-flUOIO-9oc-b1'OI110-l 16,17 a,2l-trihydroxy-16a methyl-4-pregnene-3,20-dione 2l-acetate as the starting compound, there is thusproduced6a-fiuoro-9fi,11p-epoxy,16tx-rnethyll70,21-dihydroxy-4-pregnene-3,2O-dione2l-acetate.

Similarly, substituting another 2l-acylate of 6a-fiuoro-9a-bromo-ll5,l7a,21-trihydroxy-16a-methyl-1,4 pregnadiene-3,20-dione ora 2l-acylate of 6wflUOIO-9ot-bf0lfl0-11B,17a,2l-trihydroxy-16u-methyl-4-pregnene-3,20 dione wherein the acylradical is, e.g., that of an acid named in the paragraph followingExample 11, as the starting compound in the reaction described inExample 18, there is thus produced the corresponding 2l-acylate ofSet-fluoro- 9 3,1lfi-epoxy-16a-methyl-17a,21-dihydroxy-1,4pregnadiene-3,20-dione and of 6a-fiuoro-9fi,1lfl-epoxy-16a-methyl- 17u,21-dihydroxy-4-pregnene-3,20-dione, respectively.

EXAMPLE 20 To approximately 1.3 grams of hydrogen fluoride contained ina polyethylene bottle and maintained at minus sixty degrees centigradewas added 2.3 milliliters of tetrahydrofuran and then a solution of 500milligrams (0.0012 mole) of6a-fiuoro-9B,1lfl-epoxy-16a-methyl-17a,2l-dihydroxy-l,4-pregnadiene-3,20-dione2l-acetate in two milliliters of methylene chloride. The steroidsolution was rinsed in with an additional one milliliter of methylenechloride. The light red colored solution was then kept at approximatelyminus thirty degrees centigrade for one hour and at minus ten degreesfor two hours. At the end of this period it was mixed cautiously with anexcess of cold sodium bicarbonate solution and the organic materialextracted with the aid of additional methylene chloride. The combinedextracts were Washed with water, dried over anhydrous sodium sulfate andconcentrated to approximately 35 milliliters. The solution waschromatographed over 130 grams of Florisil anhydrous magnesium silicate.The column was developed with 260-milliliter portions of hexanes(Skellysolve B) containing increasing proportions of acetone. There wasthus eluted 651,954-difluoro-l 1B,17a,21-trihydroXy-1oat-methyl 1,4pregnadiene-3,20-dione 21-acetate which was freed of solvent byevaporation of the eluate fractions.

EXAMPLE 21 Following the procedure of Example 20, but substituting6a-fluoro-9fi,1lfi-epoxy-l6a-methyl-17a,21 dihydroxy-4-pregnene-3,20-dione 21-acctate as the starting compound, there is thusproduced 6a,9tx-difiuoro-llfi,l7a,2l-trihydroxy-16a-methyl-4-pregnene-3,20-dione 21-acetate.

Similarly, substituting another 21-acylate of 6a-fluoro-96,1l{it-epoxyl7u,21-dihydroxy-l6a-methyl-1,4 pregnadiene-3,20-dione ora 21-acylate of 6a-fluoro-9fl,ll,B-epoxy- 17a,2l-dihydroxy-l6amethyl-4.pregnene 3,20 dione wherein the acyl radical is, e.g., that ofan acid named in the paragraph following Example 11, as the startingcompound in the reaction described in Example 17, there is thus producedthe corresponding 21-acylate of 6uz,9oc-difiuoro-l1,8,17a,2l-trihydroxy-16a-methyl-1,4 pregnadiene-3,20-dione andof 6a,9o-difluoro-11,8,17a,21-trihydroxy-l6a-methyl-4-pregnene-3,20-dione,respectively.

EXAMPLE 22 6a,9a-diflu0r0-16a-merhyl-I 7a,2I-dihydr0xy-I,4-pregnadiene-3,11,20-trine 2I-acetate A solution was prepared containingone milliliter of acetic acid, fifty milligrams ofouflwdifiuoro-llp,l7a,2l-

24 trihydroxy-16ot-methyl-1,4-pregnadiene-3,20-dione 2l-acetate, twentymilligrams of chromic anhydride and one drop (approximately fiftymilligrams) of water. This mixture was shaken several times at roomtemperature and allowed to stand for four hours. Thereafter it waspoured into ten milliliters of water and refrigerated for twenty hoursat about five degree centigrade. The steroid which separated from theaqueous mixture was collected on filter paper and dried to give6a,9u-difiuoro-16amethyl-17a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acetate.

EXAMPLE 23 Following the procedure of Example 22, but substituting6a,9a-difiuoro-11B,l7a,21-trihydroxy-16a-methyl-4 pregnene-3,20-di0ne21-acetate as the starting compound, there is thus produced 6a,9x-difiuoro-165t-methyl-17a,21-dihydroxy-4-pregnene-3,11,20-trione21-acetate.

Similarly, substituting another 21-acylate of 6a,9tx-dlfiuoro-l1,8,17a,21-trihydroxy-16a-methyl 1,4 pregnadiene-3,20-dione or a21-acylate of 6a,9a-difiuoro-11B,17a, 2l-trihydroxy-16a-methyl-4-pregnene-3,20-dione wherein the acyl radicalis, e.g., that of an acid named in the paragraph following Example 11,as the starting compound in the oxidation reaction described in Example22, there is thus produced the corresponding 21-acylate of6a,9oL-dlfluoro-l6a-methyl-17a,21-dihydroXy-1,4 pregnadiene 3,11,20-trione and of 60;,9oc-dlflll0l0-l6otm6thyl-170t,2l-dihydroxy-4-pregnene-3 ,1l,20-trione, respectively.

EXAMPLE 24 604,90c-diflll0l'0-11/3J 711,2]-trihydr0xy-16ot-methyl-l,4-pregnadiene-3,20-dione Three and one-quarter (3.25) grams of6a,9ct-difluoro- 1lfl,17a,21 trihydroxy 16a methyl 1,4 pregnadiene-3,20-dione 21-acetate was dissolved in 325 milliliters of methanol,previously purged of air-oxygen by passing nitrogen through it for tenminutes and thereto was added a solution of 1.63 grams of potassiumbicarbonate in thirty milliliters of water, similarly purged of oxygen.The mixture was allowed to stand at room temperature for a period offive hours in a nitrogen atmosphere, thereupon neutralized with 2.14milliliters of acetic acid in forty milliliters of water. The mixturewas concentrated to approximately one-third volume at reduced pressureon a sixty-degree-centigrade water-bath. Thereupon 250 milliliters ofwater was added and the mixture chilled. The crystalline product wascollected on a filter, washed with water and dried to give6a,9a-difluoro-11fl,17a,21-trihydroxy-16u-methyl-1,4-pregnadiene-3,20-dione.

EXAMPLE 25 Following the procedure of Example 24, but substituting60:,911 difluoro 11fi,l7cc,21 trihydroxy-16a-methyl-4-pregnene-3,20-dione 2l-acetate as the starting compound, there is thusproduced 60,9tx-difiLlOIO-11 3,17ot,21-trihydroxy-16a-methyl-4-pregnene-3,20-dione.

Similarly, 6a,9tx-difluoro-16u-n1ethyl-17a,2l-dihydroxy-4-pregnene-3,11,20-trione 21-acetate is hydrolyzed to 60:, 9a difluoro16oz methyl-l7a,2l-dihydroxy-4-pregnene- 3,11,20-trione and 60,9ocdifluoro 16a methyl 17a,2l dihydroxy-1,4-pregnadiene-3,11,20-trione21-acetate is hydrolyzed to 6a,9u-difluoro-16a-methyl-17a,21-dihydroxy-1,4 pregnadiene 3,11,20 trione. The corresponding 91:- chloro compoudsare similarly prepared by hydrolysis of their 2l-acetates, e.g.,6a-fluoro 9oz chloro 11 8,l7u,21 trihydroxy-16a methyl 1,4 pregnadiene3,20 dione and 6a-fluoro c chloro ]1B,l7a,21 trihydroxy 16ainethyl-4-pregnene-3,20-dione are prepared from 6lX-fiLlOIO- 9a chlorollp',17tx,2l trihydroxy 16cc methyl 1,4

pregnadiene-3,20-dione 21-acetate and from 605-fiuoro-905- chloro11,8,1705,21 trihydroxy 1605 methyl 4 pregnene-3,20-dione 21-acetate,respectively.

EXAMPLE 26 6 05,905-d i fluoro-I 118,1 705,21-trihydrxy-1 6 a-methy [-1,4 pregnadiene-3,20-di0ne 21-pr0pz'0nate A solution was preparedcontaining fifty milligrams of 605,905 difiuoro-115,1705,21 trihydroxy1605 methyl 1,4-pregnadiene-3,20-dione in one milliliter of pyridine andone milliliter of propionic anhydride. The solution was allowed to standat room temperature for a period of 21 hours and was thereupon pouredinto ten milliliters of water. The reaction mixture was then extractedwith three ten-milliliter portions of methylene chloride, the methylenechloride extracts were combined, washed with water, dried over anhydroussodium sulfate and evaporated to give a residue of 605,905 difiuoro11,B,1705,21 trihydroxy 1605 methyl-1,4-pregnadiene-3,20-dione2l-propionate.

EXAMPLE 27 6 05,905-511' fiuoro-1 1,8,1 705,21-trihydr0xy-1 6 -methyl-4pregnene-3,20-dione 21 -pr0pi0nate Following the procedure of Example26, but substituting 605,905 difiuoro 11fl,1705,21 trihydroxy 1605methyl 4-pregnene-3,20-dione as starting compound, there is thusproduced 605,905 difiuoro 11 8,l705,21 trihydroxy 1605methyl-4-pregnene-3,20-dione 21-propionate.

Similarly, 605,905-difluoro-l605-methyl-l705,2l-dihydroxy-1,4-pregnadiene3,11,20-trione is converted to 605,905-difiuoro 1605methyl 1705,21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21 propionateand 605,905 difiuoro 1605 methyl 1705,21 dihydroxy 4 pregnene3,11,20-trione is converted to 605,905-difluoro-1605-methyl-17,2l-dihydroxy-4-pregnene-3,11,20-trione 21-propionate.

Similarly, substituting another acylating agent for the propionicanhydride in the esterification of 605,905-difiuoro- 11;3,1705,21trihydroxy 1605 methyl 1,4 pregnadiene- 3,20 dione or605,905-difluoro-l1fi,1705,21-trihydroxy-1605- methyl 4 pregnene3,20-dione, e.g., in the manner described in the paragraph followingExample 11, there is thus produced other 21-acylates of605,905-difiuoro-1l 8,1705, 21 trihydroxy 1605methyl-1,4-pregnadiene-3,20-dione and of605,905-difluoro-1lfl,1705,21-trihydroxy-1605-methyl-4-pregnene-3,20-dione, respectively, wherein the acyl radical is, e.g.,that of an acid named in the paragraph following Example 6. Thecorresponding ll-keto compounds are similarly converted to theircorresponding 21-acylate esters.

EXAMPLE 28 605-flu0r0-1 113,] 705,21 -trihydr0xy-1 6 05-methy [-1 ,4pregnadiene-3,20-di0ne 21 -methanesulfonate A solution was preparedcontaining one gram (2.6 millimoles) of 605 fiuoro1lfi,l705,2l-trihydroxy-l605-methyl- 1,4-pregnadiene-3,20dione in sevenmilliliters of pyridine. This solution was cooled to zero degreescentigrade and treated with 0.3 milliliter of methanesulfonyl chloride.Thereafter the solution was allowed to stand at zero to five degreescentigrade for a period of two hours, after which it was diluted withwater and extracted with three 25-milliliter portions of methylenechloride. The extracts were combined, washed with cold dilutehydrochloric acid until the aqueous layer had a pH of two to three, thenwashed again with cold sodium bicarbonate solution, water and finallydried over anhydrous sodium sulfate. Evaporation of the methylenechloride extract at reduced pressure left a residue of 605-fluoro-1l3,1705,21 trihydroxy 1605 methyl-1,4-pregnadiene-3,20-dione2'1-methanesulfonate.

Similarly, substituting 605-fluoro-l1B,1705-21-trihydroxy-1605-methyl-4-pregnene-3,20-dione as the starting compound, there isthus produced 605-fiuoro-118,l705,21-trihydroxy-l605-methyl-4-pregnene-3,20-dione 21methanesulfonate. The corresponding 905-fiuoro and 905-chloro 21-methanesulfonate compounds are similarly prepared.

EXAMPLE 29 6 a-flLlOIO-l 1,8,1 705-dihydr0xy-1 6 05-methyl-21 -iod0-1,4-pregnadiene-3,20-di0ne The crude605-fiuoro-l118,1705-21-trihydroxy-1605-methyll,4-pregnadiene-3,20-dione21-methanesulfonate described in Example 28 was dissolved in fifteenmilliliters of acetone and treated with a solution of one gram of sodiumiodide in ten milliliters of acetone. The mixture was heated underrefiux with stirring for a period of fifteen minutes, the heat thenreduced and the mixture concentrated to one-third volume at reducedpressure. Ice and water were added and the precipitated productcollected on a filter, washed with water and dried to yield605-fluoro-11p,1705- dihydroxy-1605-methyl-21-i0do 1,4 pregnadiene-3,20-dione.

Similarly, substituting 605-fiuoro-11B,1705,2l-trihydroxy-1605-methyl-4-pregnene 3,20 dione 21-methanesulfonate as the startingcompound, there is thus produced 605-fluoro-l1fl,1705-dihydroxy-1605-methyl 21 iodo-4-pregnene-3,20-dione.The 905-chloro and 905-fluoro analogues of both of these compounds aresimilarly prepared.

EXAMPLE 30 One gram of 605-fluoro-11 3,1705-dihydroxy-1605-methyl-21-iodo-1,4-pregnadiene-3,20-di0ne was dissolved in 150 milliliters ofboiling acetonitrile. After cooling to forty degrees centigrade, thesolution was protected from light and 0.8 milliliter of a fifty percentaqueous solution of silver fluoride was added under stirring. Stirringwas continued for one hour at about forty degrees centigrade, then 0.7milliliter of silver fluoride solution was added. After another hour ofstirring another 0.7 milliliter portion of aqueous silver fluoridesolution was added. Heating and stirring was then continued for a periodof two hours. The brown mixture was then filtered through a bed ofdiatomaceous earth (Celite) and the filtrate evaporated at reducedpressure at a bath temperature of fifty degrees centigrade. The brownresidue was thoroughly extracted with two 100-milliliter port-ions ofwarm methylene chloride, the combined extracts washed with water anddried over anhydrous sodium sulfate. The dried solution was concentratedto approximately 100 milliliters and then chromatographed over fitygrams of magnesium silicate (Florisil). The column was eluted withhexanes containing increasing proportions of acetone to give 605,21-difluoro-1lfl,1705-dihydroxy-1605-methyl 1,4 pregnadiene-3,20-dione.

In the same manner as given in Examples 28 to 30,605,905-difluoro-11fi,1705,21-trihydroxy 1605 methyl-1,4-pregnadiene-3,20-dione was converted to 605,905,21-trifiuoro-11B,1605-dihydroxy-1605-methyl 1,4 pregnadiene- 3,20-dione.

Similarly, substituting 605-fluoro-11/3,l705-dihydroxy-1605-methyl-21-iodo-4-pregnene-3,20-dione starting compound, there isthus produced605,21-difluoro-1l/3,1705-dihydroxy-l605-methyl-4-pregnene-3,2O-dione.605,905,21 trifiuoro-ll/3,1705-dihydroxy-1605-methyl 4 pregnene-3,20-dione is similarly prepared from 605,905-difluoro-1 15,1705-dihydroxy-l605-methyl-21-iodo-4-pregnene-3,20-dione. The

. corresponding 905-chloro compounds are similarly prepared.

EXAMPLE 3 1 605,21-diflu0r0-11/3J 705-dihydr0xy-1605-methyl-1,4-pregnadiene-3,20-di0ne 27 methylene chloride. The extracts weredried and chromatographed over magnesium silicate in the mannerdescribed in Example 30 to give substantially pure 6a,2ldifluoro 115,170dihydroxy-lfia-methyl 1,4 pregnadiene-3,20-dione.

EXAMPLE 32 A solution was prepared containing 0.5 gram of 60,21-difluoro-l1fi,17a-dihydroxy-16a-methyl 1,4 pregnadiene-3,20-dione, 0.15gram of chromic acid, ten milliliters of glacial acetic acid andone-half milliliter of water. This mixture was stirred and thenmaintained for eight hours at room temperature. Thereafter the mixturewas poured into fifty millilites of ice water, neutralized by theaddition of dilute sodium hydroxide and the thus-obtained precipitatecollected on a filter and recrystallized three times from a mixture ofethyl acetate and Skellysolve B hexanes to give6a,2l-difiuoro-l6ot-methyl-17a-hydroxyl,4-pregnadiene-3,11,20-trione.

In the same manner given in Example 32, 6a,9at,2ltrifluoro 1119,17dihydroxy-l6a-methyl-l,4-pregnadiene-3,20-dione was oxidized to6a,9a,2l-trifluoro-16amethyl-l7a-hydroxy-l,4-pregnadiene-3,11,20-trione.

Similarly, 6a,21-difiu0ro 16a methyl-l7a-hydroxy-4-pregnene-3,ll,20-trione is prepared from 6a,2l-difluoro-11,8,l7a-dihydroxy-16a-methyl-4-pregnene-3,20-dione and6m,9a,2l-trifluoro 16cc methyl-l7a-hydroxy-4-pregnene- 3,11,20-trione isprepared from 6a,9a,21-trifluoro-1 15,171dihydroxy-l6a-methyl-4-pregnene-3,20-dione. The corresponding 9a-chlorocompounds are similarly prepared.

Example 33 150 milligrams of6a-fluoro-l1B,17ot-dihydroxy-16amethyl-21-iodo-1,4-pregnadiene3,20-dione was slurried with five milliters of acetic acid and stirredfor a period of 45 minutes. Then an aqueous solution of 250 milligramsof sodium thiosulfate pentahydrate was added causing the iodine color todisappear. Additional water was added (fifty milliliters) and themixture extracted with three 25- milliliter portions of methylenechloride. The methylene chloride extracts were combined, washed withwater and cold sodium bicarbonate solution until all acetic acid wasneutralized. After drying over anhydrous sodium sulfate, the solutionwas concentrated to approximately fifteen milliters and chromatographedover ten grams of magnesium silicate (Florisil). The column wasdeveloped A mixture was prepared containing 0.3 gram ofGoafluoro-l15,17a-dihydroxy-16a-methyl 1,4 pregnadiene- 3,20-dione, 100milligrams of chromic anhydride, ten milliters of glacial acetic acidand one-half milliliter of water. This mixture was stirred and thereuponmaintained for eight hours at room temperature. Thereafter the mixturewas poured into fifty milliliters of ice water, neutralized by theaddition of dilute sodium hydroxide and the thus-obtained precipitatecollected on a filter and dried to give6ot-fluoro-l6tx-methyl-l7ot-hydroxy-1,4-pregnadiene 3,11.20-trione.

Following the procedure of Example 34, 6a,9a-difiuoro-11B,17a-dihydroxy-16a-methyl-1,4 pregnadiene 3,20- dione was oxidized to6a,9a-difiuoro-l6a-methyl 17ahydroxy- 1 ,4-pregnadiene-3 ,1 1,20-trione.

Similarly, 6a-fluoro-16a-methyl-17a hydroxy-4-pregmeme-3,1 1,20-trioneis prepared from6a-fiuoro-11/8,l7a-dihydroxy-16a-methyl-4-pregnene-3,ZO-dione and60:,9a-difluoro-16amethyl-17a-hydroxy-4-pregnene 3,11,20 trione isprepared from 6a,9a-difluoro-1lB,17a-dihydroxy-16ot-methyl-4-pregnene-3,20-dione. The corresponding chloro compoundsare similarly prepared.

Examples showing the preparation of the EB-methyl compounds of theinvention:

Example 1A The 3-ethylene glycol ketal of 3,11-diket0-16B-methyZ-4,- 17(20)-[cis] -pregnadien-21-0ic acid methyl ester To a solution of 1.5grams of 3,11-diketo-16B-methyl- 4,17(20)-[cis]-pregnadien-2l-oic acidmethyl ester dissolved in 150 milliliters of benzene was added 7.5milliliters of ethylene glycol and 01150 gram of para-toluenesulfonicacid and the whole was then heated with stirring at the refluxtemperature of the reaction mixture for 5.5 hours. The water formed inthe reaction was removed by passing the condensate through a water trap.The cooled reaction mixture was washed with milliliters of a one percentaqueous sodium bicarbonate solution. The benezene layer was then pouredon a column of grams of magnesium silicate (Florisil). The column wasdeveloped with 100-milliliter portions of solvent of the followingcomposition and order: eight portions of methylene chloride plus fourpercent acetone and three portions of methylene chloride plus eightpercent acetone. The methylene chloride plus four percent acetoneeluates contained the 3-ethylene glycol ketal of 3,11-diketo-16fl-methyl-4,17(20)-[cis]-pregnadien-Zl-oic acid methyl ester which wasfreed of solvent by evaporation.

Reacting 3,11-diketo 16B-methyl-4,17(20)-[cis]-pregnadien-Zl-oic acidmethyl ester with trimethylene glycol in the presence ofpara-toluenesulfonic acid is productive of the S-trimethylene glycolketal of 3,1l-diketo-16B- methyl-4,17(20)-[cis]-pregnadien 21 oic acidmethyl ester.

Similarly, other 3-ketals of this and other esters of3,1l-diketo-16fi-methyl-4,17(20) [cis] pregnadien-21- oic acid methylester are produced by the reaction of the selected ester of3,11-diketo-16/8-methy1-4,17(20)-[cis]- pregnadien-Zl-oic acid, e.g.,methyl, ethyl, propyl, butyl, or octyl ester, with a glycol ashereinbefore described, e.g., ethylene glycol, propylene glycol,trimethylene glycol, lower-alkyl substituted ethylene glycols ortrimethylene glycols, in the presence of an acid catalyst, e.g.,paratoluenesulfonic acid, hydrogen chloride, sulfuric acid.

Example 2A 3-etl1ylc/ze glycol ketal 0f 3,11-diket0-5a,6a-ep0xy-16B-methyl-l7(20)-[cis]-allopregnen 21 oic acid methyl ester To a solutionof five grams of the 3-ethylene glycol ketal of 3, 1 l-dilceto-l63-methyl-4,17( 20)- [cis] -pregnadien-21- oic acid methyl ester in 100milliliters of chloroform was added a chilled solution of 1.9 grams ofperbenzoic acid dissolved in 31.5 milliliters of chloroform. Thesolution was maintained at about four degrees centigrade for 24 hours,and then at room temperature for 72 hours. The solution was then washedwith a five percent aqueous solution of sodium bicarbonate and then withwater. The chloroform layer was separated, dried and the solvent 29distilled to give a residue of the 3-ethylene glycol ketal of 3,11-diketo-5a,6a-epoxy-16B-methyl-17 (20) -[cis]-allopregnen-Zl-oio acidmethyl ester.

EXAMPLE 3A .To a solution of 1.73 grams of 3-ethylene glycol ketal of3,1l-diketo-5a-6a-epoxy-16;3-methylr17(20)-[cis]-allopregnen-Zl-oic acidmethyl ester in sixteen milliliters of methylene chloride was added sixmilliliters of 48 percent hydrofiuoric acid. The heterogeneous mixturewas stirred for two hours, made slightly basic with 300 milliliters offive percent sodium bicarbonate solution, and extracted with methylenechloride. The extract was washed, dried, and evaporated to dryness togive 1.62 grams of crude solid. Purification by chromatography overmagnesium silicate gave two fractions. The first was elutedwith'methylene chloride plus five percent acetone and the second waseluted with methylene chloride plus ten and twenty percent acetone.Crystallization of the first fraction from a mixture of acetone andSkellysolve B hexanes gave 3,11 -diketo 5a-hydroxy-6/3-fluoro-16,8-methyl-l7(20)-[cis]-allopregnen-2l-oic acid methyl ester.

EXAMPLE 4A 3-ethylene glycol ketal of 3,1I-diketmSa-hydrOxy-QS-flur0-16fi-methyl-1 7(20) -[cis]-allopregnen-21-0ic acid methyl ester Amixture of 1.9 grams of methyl 6fi-fluoro-3,l1-diketo-5a-hydroXy-163-methyl 17(20) [cis]-allopregnen- 21-oate, 59 milligrams ofpara-toluenesulfonic acid monohydrate and 31 milliliters of distilledethylene glycol was added to 800 milliliters of benzene. The mixture wasstirred and refluxed for two hours, with the condensate passing througha water trap to remove the water.'Then the mixture was cooled, washedwith water and evaporated to dryness to give a crude solid which onrecrystallization from a mixture of acetone and hexanes gave the3-ethylene glycol ketal of 3,11-diketo-5a-hydroxy-6flflu0ro-16B-methyl17(20)-[cis]-allopregnen-21-oic acid methyl ester.

Following the above procedure, substituting other dihydric alcohols forethylene glycol, for example, 1,2- propylene glycol, 2,3-butanediol,1,3-butanediol and 2,3- pentanediol, is productive of the respective3-alkylene ketals of 3,1l-diketo-5a-hydroxy 6/8 methyl-17(20)-[cis]-allopregnen- 21-oic acid methyl ester.

EXAMPLE 5A The 3-ethylene glycol ketal of 5a,1] 3,21 trihydroxy-6(3-fluoro-I 6fl-m-ethyl-1 7 (20)- [cis] -all0pregnenr-3-0he To a solutionof 1.96 grams of the 3-ethylene glycol ketal of 3,11-diketo 5ahydroxy-6fl-fiuoro-l6fl-methyl- 17(20)-[cis]-allopregnen 21-oic acidmethyl ester in 850 milliliters of anhydrous ether was added 3.7 gramsof lithium aluminum hydride. The mixture was stirred for a period of onehour, and 200 milliliters of water was added slowly, the ether phaseseparating. The aqueous phase was extracted with ethyl acetate and theextracts added to the ether phase. The combined ether-ethyl acetatesolution was washed with water, dried and evaporated to dryness underreduced pressure. The crude solid residue was crystallized fromacetone-Skellysolve B hexanes to give the 3-ethylene glycol ketal of5u,11;3,21-trihydroXy 6,8-fiuoro-l6 3-rnethyl-17(20)-[cis]-allopregnen-3-one.

EXAMPLE 6A The 3-ezhylene glycol ketal of 5u,11/8,21-trihydr0xy 6B-flu0r0-16fl-methyl 17(20)-[cis]-all0pregnen-3-0ne 21- acetate 1 0.87gram of the 3-ethylene ketal of 5a,11[3,-2l-trihydroxy6fi-fluoro-16fl-methyl-17(20)-[cis]-allopregnen-3- one was dissolved inten milliliters of acetic anhydride and ten milliliters of pyridine. Thesolution was maintained sixteen hours at room temperature and thenpoured into ice water to give the 3-ethylene glycol ketal of5u,1l;3,2l-trihydroxy-6[i fiuoro 16B methyl-17(20)-[cis]-allopregnen-3-one 2l-acetate.

Similarly, other 21-organic carboXylic acid esters of 5a,llfl-2ltrihydroxy fiuoro-16fl-methyl-17(20)- [cis]-allopregnen-3-one 3-ethyleneketals can be prepared wherein the 21-acyloxy group is formyloxy,propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, benzoyloxy, phenylacetoxy, or the like, by con- 'tactingthe 3-ethylene ketal of 5a,1l 3,21-trihydroxy-6fifiuoro-l6fi-methyl-l7(20)-[cis]-allopregnen 3-one with theappropriate acylating agent, e.g., the anhydride or acid halide of theselected acid in a solvent such as benzene, toluene, acetic acid, or thelike, preferable in the presence of pyridine or a similar amine.

EXAMPLE 7A The 3-ethylene glycol ketal of5a,11/3,17a,21-tetrahydroxy-tSfl-fluoro-I6,8-methylallopregnane 3,20dione ZI-acetate To a solution of 0.93 gram of the 3-ethylene glycolketal of 5a,11,8 dihydroxy 6 3 fluoro IGB-methyl-17(20)-[cis]-allopregnen-3-one Zl-acetate in 35 milliliters of tertiarybutyl alcohol was added one milliliter of pyridine, 2.75 milliliters oftwo molar N-methylmorpholine oxide peroxide (US. 2,769,823) in tertiarybutyl alcohol, and 13.1 milligrams of osmium tetroxide in tertiary butylalcohol (9.9 milliliters of tertiary butyl alcohol solution containing1.44 milligrams osmium tetroxide per milliliter). Thesolution wasstirred for a period of eighteen hours and fifteen milliliters of fivepercent sodium hydrosulfite was added. Stirring was continued for anadditional ten minutes, at which time 0.7 gram of finely groundsynthetic magnesium silicate was mixed into the solution for a period oftwenty minutes and then removed by filtration. The filtrate wasevaporated to dryness under reduced pressure at a temperature of lessthan fifty degrees centigrade. The residue was dissolved in methylenechloride, washed with water, dried and evaporated to dryness. Theresidue was crystallized from acetone-Skellysolve B hexanes to give the3-ethylene glycol ketal of 5oc,11fl,17a, 21 tetrahydroxy 6fi-fluoro16,8-methylallopregnane- 3,20-dione 21-acetate.

EXAMPLE 8A 6 a-fl uoro-I 1 [3,1 7 a,21 -trihydroxy-1 63-methyl-4-pregnene- 3,20-di0ne 21-acetate A solution of 0.144 gram ofthe 3-ethylene glycol ketal of511,11B,17a,21-tetrahydroxy-6fi-fiuoro-16/8-methyla1lopregnane-3,20-dione21-acetate in twelve milliliters of chloroform and 0.1 milliliter ofabsolute alcohol was cooled to minus ten degrees centigrade in anice-salt bath and a stream of anhydrous hydrochloric acid was gentlybubbled through the solution for 2.5 hours while the temperature wasmaintained between minus five and minus fifteen degrees centigrade. Thesolution was then diluted with 25 milliliters of chloroform, washed withdilute sodium bicarbonate and water, dried over anhydrous sodiumsulfate, and evaporated to dryness under reduced pressure at sixtydegrees centigrade or less to give 6a fiuoro 11,B,17a,21 trihydroxy-16Bmethyl- 4-pregnene-3,20-dione ZI-acetate.

EXAMPLE 9A A medium consisting of one percent dextrose hydrate, twopercent cornsteep liquor of sixty percent solids and tap water wasadjusted to pH 4.9 with sodium hydroxide. The medium was steamsterilized at fifteen pounds pressure for thirty minutes, cooled, andthen inoculated with a 24-hour growth, from spores, of Srptomyxaa/finis, A.T.C.C. 6737. The medum was agitated, and sparged with sterileair at the rate of one-tenth volume of air per volume of medium perminute. At the end of 24 hours of fermentation at room temperature, thepH was about 7.4. To this culture there was added a solution of 6afluoro11fl,17a,21 trihydroxy 16p methyl 4 pregnene-3,20-dione 2l-acetatedissolved in a minimal amount of diethylformamide. The solution wasprepared by dissolving five parts of the steroid in 100 parts of thesolvent and adding about ten cc. of the solution per liter of themedium. Fermentation was continued for a period of 48 hours whereuponthe mycelium and beer were extracted thoroughly with methylene chloride.The extract was washed with sodium bicarbonate solution and then withwater, dried and concentrated in vacuo to give 6a-flu0r0- 1l 3,17o 21trihydroxy 16,8 methyl 1,4 pregnadiene-3,20-dione.

Following the procedure of Example 9A, but substituting as startingmaterial 6tx-fiuoro-l1,8,17a,21-trihydroxy-16fl-methyl-4-pregnene-3,20-dione there was likewise produced 60c fluoro11,8,17a,21-trihydroxy-16B-methyl-1,4- pregnadiene-3,20-dione.

EXAMPLE 10A A solution of 1.1 grams of6a-fluoro-11fi,17a,21-trihydroxy-l6/3-methyl-4-pregnene-3,ZO-dione21-acetate, one gram of potassium bicarbonate, 100 milliliters ofmethanol and fifteen milliliters of water were mixed together and purgedwith nitrogen to remove dissolved oxygen while stirring at degreescentigrade for four hours. The solution was then neutralized by additionof acetic acid and distilled under vacuum to remove the methanol. Theresidue was extracted with 100 milliliters of methylene chloride, andthe extract was dried over sodium sulfate to give a solution of6u-fiuoro-11B,17a,21-trihydroxy- 16fl-methyl-4-pregnene-3,ZO-dione whichwas freed of solvent by evaporation.

EXAMPLE 11A 1.5 grams of 6u-flUOIO-115,17a,21-trihydroxy-16(5-methyl-l,4-pregnadiene-3,20-dione wasdissolved in twenty milliliters of pyridine and fifteen milliliters ofacetic anhydride and the mixture heated at forty degrees centigrade forfour hours. The solution was cooled and then slowly diluted with water.The precipitated steroid was removed by filtration, washed with waterand dried to give 6a fluoro l1fl,17a,21 trihydroxy-16;3-methyl-1,4-pregnadiene-3,20-dione 21-acetate.

6oz fiuoro 1lfi,17a,21 trihydroxy 16/3 methyl 1,4-pregnadiene-3,20-dione is converted to other 21-esters by reactionwith the appropriate acid anhydride, acid chloride, or bromide or byother methods known in the art, e.g., by ester exchange, acid in thepresence of an esterification catalyst, etc., to produce6ocfluOIO-1lfl,l7oz, 21-trihydroxy-165-methyl-1,4-pregnadiene-3,20dione21- acylates which include those wherein the acyl radical of the2l-acylate group is the acyl radical of, for example, a lower aliphaticacid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric,trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic,diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, acyclic acid, e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, [i-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl oralkaryl acid, e.g., 'benzoic 2, 3, or 4- methylbenzoic, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, ot-naphthoic, 3 methylornaphthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic,diphenylacetic, triphenylacetic, a dibasic acid (which can be convertedto water soluble, e.g., sodium, salts), e.g., succinic, glutaric,ot-methylglutaric, ,B-methylglutaric, fl-p-dimethylglutaric, adipic,pimelic, suberic, a hydroxyacid, e.g.,' glycolic, lactic, citric,tartaric, d-maleric, d-glyceric, mannonic, gluconic, salicylic,2,3,4-trimethoxybenzoic, anaphthoxyacetic, or other acyl acid.Alternatively, the 21- hydroxy group is converted to the 21-phosphateester group according to procedures known in the art, e.g., as describedin US. 2,870,177.

Similarly, L-fiUOl'O-1 1,6,17,21-trihydroxy-16fi-methyl-4-pregnene-3,20-dione is converted to any of the other esters named inthe paragraph following Example 11A by substituting115,17a,2l-trihydroxy-16B-methyl-4-pregnene-3,20-dione as the startingcompound in the acylation reaction.

EXAMPLE 12A 6oc-flltOl'O-1 6 3-methyl-I 7a,21-dihydroxy-I,4-pregnadiene-3,11,20-tri0ne ZI-acetate To a solution of 2.5 millirnoles of60,fiUOIO-1 1,6,17a,21-trihydroxy-16/3-methyl-1,4-pregnadiene-3,ZO-dione 2l-acetate and twomilliliters of pyridine in milliliters of tertiary butanol was added 500milligrams of N-bromoacetamide. The reaction mixture was maintained atroom temperature for about sixteen hours whereupon the solution wasdiluted with fifty milliliters of water containing 500 milligrams ofsodium sulfite, and the mixture was then concentrated at reducedpressure to about forty milliliters. The distillation residue wasrefrigerated, filtered, and the filter cake was washed with water andthen dried. It consisted of 6a-fiuoro-16B-methyl-17a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acetate.

EXAMPLE 13A 6 oc-fl uoro-I 6 B-met/zy l-I 7a,21-dihydr0xy-4-pregnene-3,11 20-lri0ne 21 -acetate Following the procedureof Example 12A, but substituting 6oz fluoro1lfl,17a,21-trihydroxy-16B-methyl-4- pregnene-3,20-dione 21-acetate asstarting compound, there is thus produced6a-fluoro-16,B-methyl-17a,21-dihydroxy-4-pregnene-3,l1,20-trione21-acetate.

Similarly, substituting another 21-acylate of Ga-fiUOfO- 11,8,17a 21trihydroxy 16 8 methyl 1,4- pregnadiene-3,20-dione or 21-acylate of6a-fiuoro-11B,l7u,21-trihydroxy-16fl-methyl-4-pregnene-3,20-dionewherein the acyl radical is, e.g., that of an acid named in theparagraph following Example 11A, as the starting compound in theoxidation reaction described in Example 12A, there is thus produced thecorresponding 21-acylate of Gafluoro-l6,8-methyl-17a,21-dihydroxy 1,4pregnadiene-3, 11,20-trione and of6tx-fiuoro-16fi-methyl-17a,2l-dihydroxy-4-pregnene-3,11,20-trione,respectively.

EXAMPLE 14A To a solution of 8.5 grams of6tx-fluoro-115,17a,21-trihydroxy 16,8-mthyl 1,4-pregnadiene-3,20 dione21- acetate in 42.5 milliliters of pyridine was added 5.63 grams ofN-bromoacetamide. After standing at room temperature for a period offifteen minutes, the reaction solution was cooled to five to ten degreescentigrade and sulfur dioxide gas was passed over the surface of thesolution while shaking the flask until the solution gave no color withacidified starch-iodide paper. During the addition of the sulfurdioxide, the reaction mixture became warm. The temperature was keptunder thirty degrees centigrade by external cooling and by varying therate of sulfur dioxide addition. Thereafter to the reaction mixture wasadded 400 milliliters of ice water and the resulting precipitatecollected by filtration. This material was recrystallized fromacetone-Skellysolve B hexanes to give 6a-fluoro-16,8-methyl-17a,21-dihydroxy 1,4,9 1 1 )-pregnatriene-3,20-dione2l-acetate.

EXAMPLE 15A Following the procedure of Example 14A, but substituting6a-fiuoro-1lfl,17a,21-trihydroxy 16fi-methyl-4- pregnene-3,20-dione2l-acetate as the starting compound, there is thus produced6a-fluoro-16/8-methyl 17,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione21-acetate.

Similarly, substituting another 2l-acylate of 6oz-fiu0r0-11,8,170;,2l-trihydroxy-IGB-methyl 1,4-pregnadiene-3,2O-

EXAMPLE 16A To a solution of 5.68 grams of 6a-fluoro 16fl-rnethyl-1704,21-dlhYd1'0XY 1,4,9(l1) pregnatriene 3,20-dione 21-acetate in 100milliliters of methylene chloride and 250 milliliters of tertiary butylalcohol was added a solution of fourteen milliliters of 72 percentperchloric acid in 100 milliliters of water followed by a solution of2.34 grams of N-bromoacetamide in sixty milliliters of tertiary butylalcohol. After stirring the reaction mixture for fifteen minutes, asolution of 2.8 grams of sodium sulfite in 140 milliliters of water wasadded and the reaction mixture was concentrated to a volume of about 500milliliters under reduced pressure at about fifty degrees centigrade.The concentrate was cooled in an ice bath and while stirring 500milliliters of water was added. After stirring for a period of one hour,the precipitated product was isolated by filtration, and the cake washedwith water and air-dried to give 6a-flu0ro-9a-bromo-11/3,17a,21-trihydroxy 16B-methyl 1,4-pregnadiene 3,20- dione 21-acetate.

EXAMPLE 17A 6w ur0-9a-brom0-1 1 ,8,1 7a,21-trihydroxy-1tier-methyl-4-pregnene-3,20-dz'-0ne 21 -acetate Following the procedure of Example16A, but substituting 6a-fiuoro lfi-methyl 17u,21-dihydroxy 4,9(ll)-pregnadiene-3,20-dione 21 acetate as the starting compound, thereis thus produced Ga-flUOI'O 9a-bromo- 11B,17a,21-trihydroxy 16fi-methyl4-pregnene 3,20- dione 21-acetate.

Similarly, substituting another 2.1-acylate of 6a-fluoro- 16,B-methylNail-dihydroxy 1,4,9(11)-pregnatriene- 3,20-dione or a 21-acylate ofGot-fluoro-Hall-dihydroxy- 16B-methyl-4,9(ll)-pregnadiene 3,20-dionewherein the acyl radical is, e..g., that of an acid named in theparagraph following Example 11A, as the starting compound in thereaction described in Example 16A, there is thus produced thecorresponding 2l-acylate of 6ot-flllO1'O-90cbromo11/3,17ot,21-trihydroxy 16/3-methyl 1,4-pregnadiene-3,20-dione and of6ot-flll0lO-9oz-bIOII10-l1fi,l7ot,2ltrihydroxy 16B-methyl4-pregnene-3,20-dione, respectively.

Substituting N-chlorosuccinimide for the N-bromoacetamide in thereactions described in Examples 16A and 17A and the paragraph followingis productive of the corresponding 9a-chloro compounds, e.g.,6a-fluoro-9uchloro 11/3,17a,21-trihydroxy 16a-methyl1,4-pregnadiene-3,20-dione 2l-acetate and 60t-fiLIOIO-9ot-ChlOIO-ll/3,

l7u,21-trihydroxy 16f3-methyl 4-pregnene 3,20-dione 21-acetate.

EXAMPLE 18A To a solution of 6.78 grams of 6a-fluoro-9u-bromo-11B,17a,21-trihydroxy 16,8-methyl-1,4-pregnadiene-3,20- dione ZI-acetatein 175 milliliters of acetone was added 6.78 grams of potassium acetateand the resulting suspension was heated under reflux for a period ofseventeen hours. The mixture was then concentrated to approximatelysixty milliliters volume at reduced pressure on the steam bath, dilutedwith water and extracted with methylene chloride. The methylene chlorideextracts were combined, washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue was redissolved in methylenechloride and chromatographed over 500 grams of Florisil anhydrousmagnesium silicate. The column was eluted with one-liter portions ofhexanes (Skellysolve B) containing increasing proportions of acetone.There was thus eluted 6a-fiuoro-9fl,l1 8-epoxy-16fl-methyl-17a,21-dihydroxy 1,4-pregnadiene-3,ZO-dione 21-acetate which was freedof solvent by evaporation of the eluates.

EXAMPLE 19A Following the procedure of Example 18A, but substituting6a-fiuoro-9a-bromo 113,17a,21-trihydroxy-16{3 methyl 4-pregnene3,20-dione 21-acetate as the starting compound, there is thus produced6u-fiuoro-9B,11B- epoxy-16fl-methyl 17a,2l-dihydroxy 4-pregnene-3,20-dione 21-acetate.

Similarly, substituting another 2l-acylate of Got-fluoro- 9a-bromo11l3,17a,21 trihydroxy 16fi-methyl 1,4- pregnadiene-3,20-dione or a21-acylate of 6a-fiuoro-9abromo 11B,17a,21-trihydroxy16B-methyl-4-pregnene- 3,20-dione wherein the acyl radical is, e.g.,that of an acid named in the paragraph following Example 11A, as thestarting compound in the reaction described in Example 18A, there isthus produced the corresponding 21- acylate of 6u-fluoro9,8,11,8-epoxy-l6fi-methyl 170:,21- dihydroxy 1,4-pregnadiene-3,20-dioneand of 6a-fluoro- 9,B,l1B epoxy-16fi-methyl-17,21-dihydroxy-4-pregnene-3,20-dione, respectively.

EXAMPLE 20A 6a,9a-diflu0r0=-11/3,1 7a,21-trihydr0xy-1 6B-methyl-1,4-pregnadiene-3,20-dione 21 -acetate To approximately 1.3 grams ofhydrogen fluoride contained in a polyethylene bottle and maintained atminus sixty degrees centigrade was added 2.3 milliliters oftetrahydrofuran and then a solution of 500 milligrams (0.0012 mole) of6a-fluoro-9fi,11B-epoxy-16B methyl- 17a,21-dihydroxy 1,4-pregnadiene3,20-dione 21-acetate in two milliliters of methylene chloride. Thesteroid solution was rinsed in with an additional one milliliter ofmethylene chloride. The light red colored solution was then kept atapproximately minus thirty degrees centigrade for one hour and at minusten degrees at two hours. At the end of this period it was mixedcautiously with an excess of cold sodium bicarbonate solution and theorganic material extracted with the aid of additional methylenechloride. The combined extracts were washed with water, dried overanhydrous sodium sulfate and concentrated to approximately 35milliliters. The solution was chromatographed over grams of Florisilanhydrous magnesium silicate. The column was developed with 260-milliliter portions of hexanes (Skellysolve B) containing increasingproportions of acetone. There was thus eluted 6a,9a difluoro1lfl,17oc,21 trihydroxy 1613 methyl- 1,4-pregnadiene-3,20-dione21-acetate which was freed of solvent by evaporation of the eluatefractions.

EXAMPLE 21A 611,911 difiuoro ]1fi,I711,2I trihydroxy 161i methyl-4-pregnene-3,20-di0ne 21 -acetate Following the procedure of Example20A, but substituting 611 fluoro-9/3,11B epoxy 16fi-methyl 1751,21-dihydroxy 4-pregnene-3,20-dione 2l-acetate as the starting compound,there is thus produced 601,901-difiU01O-11B, 1711,21 trihydroxy16f3-methyl 4-pregnene-3,20-dione 21-acetate.

Similarly, substituting another 2l-acylate of 611-fluoro- 95,11/3 epoxy1711,2l-dihydroxy 16,8-methyl 1,4- pregnadiene 3,20-dione or a21-acylate of 611-fluoro-9fi, 11,6 epoxy-1711,21-dihydroxy 16fi-methyl4-pregnene- 3,20-dione wherein the acyl radical is, e.g., that of anacid named in the paragraph following Example 11A, as the startingcompound in the reaction described in Example 20A, there is thusproduced the corresponding 21-acylate of 611,911 difiuoro 1113,1711,21trihydroxy- 16fi methyl-1,4 pregnadiene 3,20-dione and of 611,911-difluoro 11fl,1711,21-trihydroxy 16fi-methyl-4-pregnene- 3,20-dione,respectively.

EXAMPLE 22A 611,911 difiuoro 16B methyl 1711,21-dihydr0xy 1,4-pregnadiene3,11,20-tri0ne 21 -acetate A solution was prepared containingone milliliter of acetic acid, fifty milligrams of 611,911-difiuoro115,171, 21 trihydroxy 16,8 methyl 1,4-pregnadiene 3,20- dione21-acetate, twenty milligrams of chromic anhydride and one drop(approximately fifty milligrams) of water. This mixture was shakenseveral times at room temperature and allowed to stand for four hours.Thereafter it was poured into ten milliliters of water and refrigeratedfor twenty hours at about five degrees centigrade. The steroid whichseparated from the aqueous mixture was collected on filter paper anddried to give 611,9oc-dlflll0l'0- 16,8 methyl 1711,2l-dihydroxy1,4-pregnadiene-3,l1, 20-trione ZI-acetate.

EXAMPLE 23A 611,911 difiuoro 16B methyl 1711,21 dihydroxyl-preg-Ilene-3,11,20-tri0ne 21 -acetate Following the procedure of Example 22A,but substituting 611,911 difiuoro 115,1711,21 trihydroxy 165-methyl-4-pregnene-3,20-dione 21-acetate as the starting compound, thereis thus produced 611,911-difiuoro-16flmethyl 1711,21 dihydroxy4-pregnene 3,11,20-trione 21-acetate.

Similarly, substituting another 21-acylate of 611,911-difiuoro11,8,1711,21 trihydroxy 16/3 methyl 1,4-pregnadiene-3,20-di0ne or a21-acylate of 611,911-difiuoro-11fl, 1711,21 trihydroxy 16B methyl4-pregnene 3,20- dione wherein the acyl radical is, e.g., that of anacid named in the paragraph following Example 11A, as the startingcompound in the oxidation reaction described in Example 22A, there isthus produced the corresponding Zl-acylate of 611,911 difiuorol6B-methyl 1711,21 dihydroxy 1,4-pregnadiene 3,11,20-trione and of611,911- difiuoro 1613 methyl 1711,21 dihydroxy 4-pregnene3,11,20-trione respectively.

EXAMPLE 24A 611,911 difiuoro ]Ifi,I7a,2I trihydroxy 165 methyl-I,4-preg/mdiene-3,20-dione Three and one-quarter (3.25) grams of611,911-difiuoro- 11/3,1711,2l trihydroxy 16fi-methyl 1,4-pregnadiene-3,20-dione 21-acetate was dissolved in 325 milliliters of methanol,previously purged of air-oxygen by passing nitrogen through it for tenminutes and thereto was added a solution of 1.63 grams of potassiumbicarbonate in thirty milliliters of water, similarly purged of oxygen.The mixture was allowed to stand at room temperature for a period offive hours in a nitrogen atmosphere, and then 36 neutralized with 2.14milliliters of acetic acid in forty milliliters of water. The mixturewas concentrated to approximately one-third volume at reduced pressureon a sixty-degree-centigrade water-bath. Thereupon 250 milliliters ofwater was added and the mixture chilled. The crystalline product wascollected on a filter, washed with water and dried to give611,911-difluoro 11B,17o1,21-trihydroxy-16B-methyl-l ,4-pregnadiene-3,20-dione.

EXAMPLE 25A 611,911 difiuoro I1b,I711,2I trihydroxy 165 met/1y!-4-preg/zene-3,20-ai0/ze Following the procedure of Example 24A, butsubstituting 611,911 difiuoro 1lfl,1711,21 trihydroxy 16/3-methyl-4-pregnene-3,20-dione 21-acetate as the starting compound, thereis thus produced 611,911-difiuoro 11,6,1711,21-trihydroxy-l6fl-methyl-4-pregnene-3,20'dione.

Similarly, 6a,911-difiuoro-16B-methyl 1711,21dihydroxy-4-pregnene-3,11,20-trione 21-acetate is hydrolyzed to6u1,911-difiuoro 16B methyl-171131-dihydroxy-4-pregnene-3,l1,20-trioneand 611,911 difiuoro-16fl-methyl-1711, 2l-dihydroxy-1,4-pregnadiene3,11,20 trione 21-acetate is hydrolyzed to 611,911-difiuoro 16 3methyl-1711,21-dihydroxy 1,4 pregnadiene-3,11,20-trione. Thecorresponding 911-chloro compounds are similarly prepared by hydrolysisof their 21-acetates, e.g., 611-fiuoro-911-chloro-11fi,1711,21-trihydroxy-16fi-methyl-1,4-pregnadiene 3,20- dione and651-fluoro-911-chl0ro-1'1{3,1711,21 trihydroxy- 16,8-methyl 4pregnene-3,20-dione are prepared from611-fluoro-911-chloro-11B,1711,21-trihydroxy 165 methyl-1,4-pregnadiene-3,20-dione 21-acetate and from 611-fluoro- 911chloro-l1B,1711,21-trihydroxy-16fi-methyl 4 pregnene-3,20-dione21-acetate, respectively.

EXAMPLE 26A A solution was prepared containing fifty milligrams of611,911-difluoro 11fi,1711,21 trihydroxy-16B-methyl-1,4-pregnadiene-3,20-dione in one milliliter of pyridine and one milliliterof propionic anhydride. The solution was allowed to stand at roomtemperature for a period of 21 hours and was thereupon poured into tenmilliliters of Water. The reaction mixture was then extracted with threeten-milliliter portions of methylene chloride, the methylene chlorideextracts were combined, washed with water, dried over anhydrous sodiumsulfate and evaporated to give a residue of611,911-difluoro-11fi,1711,21-trihydroxy-16,8-methyl-1,4-pregnadiene-3,20-dione 21-propionatc.

EXAMPLE 27A 601,911-diflt101'0-1 1B,] 711,21 -trihydroxy-1 6fl-methylipregnene-3,20-di0ne ZJ-propionate Following the procedure ofExample 26A, but substituting 611,911-difluoro-11fi,1711,21-trihydroxy16fi-methyl-4-pregnene-3,20-dione as starting compound, there is thusproduced 611,911-difluoro-11,8,1711,21-trihydroxy-16Bmethyl-4-pregnene-3,20-dione 21-propionate.

Similarly, 611,911 difluoro-16,8-methyl-1711,21dihydroxy-1,4-pregnadiene-3,11,20-trione is converted to 611,911-difluoro 16B methyl-1711,21-dihydroxy-1,4-pregnadiene-3,11,20-trione21-propionate and611,951-difiuoro-16flmethyl-1711,21-dihydroxy-4-pregnene 3,11,20 trioneis converted to 611,911-difluoro-16fl-methyl-l711,21-dihydroxy-4-pregnene-3,11,20-trione 21-propionate.

Similarly, substituting another acylating agent for the propionicanhydride in the esterification of 611,911-difluoro-1lB,17a,21-trihydroxy-16/8-methyl 1,4 pregnadiene-3, 20-dione or6a,911-difiuoro 11B,1711,21-trihydroxy-16fimethyl-4-pregnene-3,20 dione,e.g., in the manner described in paragraph following Example 11A, thereis thus produced other 21-acylates of 611,911-difluoro-11/3,1711,21-trihydroxy-16fi-methyl 1,4 pregnadiene 3,20- dione and of611,911-difiuoro 115,171,21 trihydroxy-165 37methyl-4-pregnene-3,ZO-dione, respectively, wherein the acyl radical is,e.g., that of an acid named in the paragraph following Example llA. Thecorresponding 11- keto compounds are similarly converted to theircorresponding 21-acylate esters.

EXAMPLE 28A 6 oc-flllOl'O-l 15,1704,21-trihydrxy-16B-methyl-L4-pregnadiene-3,20-a'ionc 21 -methanesulf0na re A solution was preparedcontaining one gram (2.6 millimoles) of 6a-fiuoro-1lfi,l7a,2l-trihydroxy16B-methyl- 1,4-pregnadiene-3,20-dione in seven milliliters of pyridine.This solution was cooled to zero degrees centigrade and treated with 0.3milliliter of methanesulfonyl chloride. Thereafter the solution wasallowed to stand at zero to five degrees centigrade for a period of twohours, after which it was diluted with water and extracted with three-milliliter portions of methylene chloride. The extracts were combined,washed with cold dilute hydrochloric acid until the aqueous layer had apH of two to three, then washed again with cold sodium bicarbonatesolution, water and finally dried over anhydrous sodium sulfate.Evaporation of the methylene chloride extract at reduced pressure left aresidue of 6zx-fluoro-1lfl,17a,2l-trihydroxy-l65-methyl-1,4-pregnadiene-3,20-dione ZI-methanesulfonate.

Similarly, substituting 6a-fluoro-1l/3,l7a,21-trihydroxy-16,8-methyl-4-pregnene-3,20-dione as the starting compound, there isthus produced 6a-fluoro-1lB,l7a,21-trihydroXy-16fi-methyl 4pregnene-3,20-dione 21-methanesulfonate. The corresponding 9a-chloro and9a-fluoro 21- O methanesulfonate compounds are similarly prepared.

EXAMPLE 29A 6 u-flzzoro-l 15,1 7a-dihydr0xy-16,6-m ethyZ-21Jada-1,4-pregnadiene-3,20-di0ne as the starting compound, there is thus produced6a- 0 fluoro-llBJh-dihydroxy 16B methyl 2l iodo-4- pregnene-3,20-dione.The 9a-chloro and 9a-fluoro analogues of both of these compounds aresimilarly prepared.

EXAMPLE 30A One gram of 6a-fluoro-l1/3,l7a-dihydroXy-l6fl-methyl-2l-iodo-l,4-pregnadiene-3,20-dione was dissolved in 150 milliliters ofboiling acetonitrile. After cooling to forty degrees centigrade, thesolution was protected from light and 0.8 milliliter of a fifty percentaqueous solution of silver fluoride was added under stirring. Stirringwas continued for one hour at about forty degrees centigrade, then 0.7milliliter of silver fluoride solution was added. After another hour ofstirring another 0.7 milliliter portion of aqueous silver fluoridesolution was added. Heating and stirring was then continued for a periodof two hours. The brown mixture was then filtered through a bed ofdiatomaceous earth (Celite) and the filtrate evaporated at reducedpressure at a bath temperature of fifty degrees centigrade. The brownresidue was thoroughly extracted with two 100-milliliter portions ofwarm methylene chloride, the combined extracts washed with water anddried over anhydrous sodium sulfate. The dried solution was concentratedto approximately milliliters and then chromatographed over fifty gramsof magnesium silicate (Florisil). The column was eluted with hexanescontaining increasing proportions of acetone to give65,21-difluoro-ll,8,l7a-dihydroxy-l6fi-methyl 1,4 pregnadiene-3,20-dione.

In the same manner as given in Examples 28A to 30A, 6049a difluor-o11,8,l7a,2l-trihydroxy-l6fi-methyl 1,4- pregnadiene-3,20-dione wasconverted to6a9a,21-trifluoro-l1,8,l7u-dihydroXy-l6,8-methyl-1,4-pregnadiene3,20dione.

Similarly, substituting 65t-fluoro-1 lfi,17a-dihydroxy-16B-methyl-2l-iodo-4-pregnene-3,20-dione starting compound, there is thusproduced6a,21-difluoro-11/3,l7a-dihydroxyl6fl-methyl-4-pregnene-3,20-dione.60:,9oc,21 trifluoro 11,8,17a-dihydroXyl6fi-methyl-4-pregnene-3,20-dione is similarly prepared from60,9ot-diflll0lO-1lfi,17ocdihydrOXY- Ion-methyl 2l-iodo-4-pregnene-3,20dione. The corresponding 9u-chloro compounds are similarly prepared.

EXAMPLE 31A A solution of one gram of6a-fluoro-1l5,17u,2l-trihydroxy-16fl-methyl-L4 pregnadiene 3,20-dione21-methanesulfonate and 0.50 gram of anhydrous potassium fluoride in tenmilliliters of dimethylsulfoxide was heated at 100 degrees centigradefor twelve hours. The cooled solution was diluted with water and thenextracted with methylene chloride. The extracts were dried andchromatographed over magnesium silicate in the manner described inExample 30A to give substantially pure 6a,2ldifluoro-l1p',17a-dihydroxy-16fi-methyl-l,4 pregnadiene- 3,20-dione.

EXAMPLE 32A A solution was prepared containing 0.5 gram of -6a,21-difluoro-l1,8,l7a-dihydroXy-l6{3-methyl-1,4 pregnadiene 3,20-dione, 0.15gram of chromic acid, ten milliliters of glacial acetic acid andone-half milliliter of water. This mixture was stirred and thenmaintained for eight hours at room temperature. Thereafter the mixturewas poured into fifty milliliters of ice water, neutralized by theaddition of dilute sodium hydroxide and the thus-obtained precipitatecollected on a filter and recrystallized three times from a mixture ofethyl acetate and Skellysolve B hexanes to give6a,2l-difluoro-165-methyl-17a-hydroxy- 1,4-pregnadiene-3, l 1,20-trione.

In the same manner given in Example 32A, 6a,9oc,2ltrifluor-o-l l5,l7a-dihydroxy-16/3-methyl-1,4 pregnadiene- 3,20-dione was oxidized to6a,9a-21-trifluoro-16fl-methyl-17a-hydroXy-l,4-pregnadiene-3,l1,20-trione.

Similarly, 611,21 difluoro-16fi-methyl-17u-hydroxy-4pregnene-3,ll,20-trione is prepared from 601,21-dlfl1l010- 11B,l7a-dihydroxy-16,8-methyl-4-pregnene-3,20-dione and6a,9a,2l-trifluoro-l6B-methyl-l7a hydroxy-4-pregnene- 3.1 1,20-trione isprepared from 6a,9oc,2l-tfifluOIO-115,170:-dihydroxy-l6B-methyl-4-pregnene-3,20-dione. The corresponding 9a-chlorocompounds are similary prepared.

EXAMPLE 33A milligrams of 6ot-fluoro-llfi,l7a-dihydroXy-l65-methyl-2l-iodo-l,4-pregnadiene-3,20-dione was slurried with fivemilliliters of acetic acid and stirred for a period of 45 minutes. Thenan aqueous solution of 250 milligrams of sodium thiosulfate pentahydratewas added causing the iodine color to disappear, Additional water wasadded (fifty milliliters) and the mixture extracted with three25-milliliter portions of methylene chloride. The

methylene chloride extracts were combined, washed with water and coldsodium bicarbonate solution until all acetic acid was neutralized. Afterdrying over anhydrous sodium sulfate, the solution was concentrated toapproximately fifteen milliliters and chromatographed over ten grams ofmagnesium silicate (Florisil). The column was developed with hexanescontaining increasing proportions of acetone, to give substantially pure6a-fiu0ro-11B- 17u-dihydroxy-16fl-methyl 1,4-pregnadiene-3,20-dione.

Following the procedure of Example 33A,6ot,9u-difluoro-11fl,l7a-dihydroxy-16B-methyl-21-iodo-L4pregnadiene-3,2()-dione was converted to 6u,95t-difluor0-11fi,-17m-dihydroxy-1GB-methyl-l,4-pregnadiene-3,20-dione.

Similarly, 6oc-flLl0I0-11,B,l7oc dihydroxy-16fi-methyl-4-pregnene-3,20-dione is prepared from 6a-fiuoro-11fl,17adihydroxy-IGBmethyl-21-iodo-4 pregnene-3,20-dione and6a,9a-difiuoro-11B,17a-dihydroxy-16,8 methyl 4- pregnene-3,20-dione from6a,9adifluoro 11,6,17a-dihydroxy-l6fl-methyl21-iodo-4-pregnene-3,20-dione. The corresponding 9a-chloro compounds aresimilarly prepared.

EXAMPLE 34A A mixture was prepared containing 0.3 gram of 6afiuoro116,17 adihydroXy-16,B-methyl-1,4-pregnadiene- 3,20-dione, 100milligrams of chromic anhydride, ten milliliters of glacial acetic acidand one-half milliliter of water. This mixture was stirred and thereuponmaintained for eight hours at room temperature. Thereafter the mixturewas poured into fifty milliliters of ice water, neutralized by theaddition of dilute sodium hydroxide and the thus-obtained precipitatecollected on a filter and dried to give6a-fluoro-16fi-methyl-17a-hydroxy 1,4-pregnadiene- 3,11,20-trione.

Following the procedure of Example 34A,6a,9a-difluoro-1l/3,17a-dihydroxy-16fi methyl-1,4 pregnadiene-3,20-dione was oxidized to6a,9oc-difiu0l016,8-methyl-17ahydroxy-1,4-pregnadiene-3,11,20-trione.

Similarly, 6a-fluoro-16fl-methyl l7a-hydroxy 4-pregnene-3,11,20-trioneis prepared from 6u-fiuoro-11 8,17 xdihydroxy 165methyl-4-pregnene-3,20-dione and 6a, 90:. difiuoro16,8-methyl-17a-hydroxy-4-pregnene-3,11, -trione is prepared from6a,9u-difluoro 11B,17u-dihydroxy 165 methyl 4 pregnene-3,20-dione. Thecorresponding 9a-chloro compounds are similarly prepared.

We claim:

1. 6oz fluoro 11,8,17a,21 trihydroxy-16,8-methyl-4- pregnene-3,20-dione.

2. 6oz fluoro 11,B,17oc,2l trihydroxy-16fl-methyl-4- pregnene-3,20-dione21-acylate wherein the acyl radical is that of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive.

3. 6a fluoro 11,3,l7a,21 trihydroxy-16fi-methyl-4- pregnene-3,20-dioneZI-acetate.

4. 60a fluoro 165 methyl 17u,21-dihydr0xy-4-pregnene-3,11,20-trione 2l-acetate.

5. 6oz fluoro 16B methyl 170c,21 dihydroxy-4- pregnene-3,11,20-trione.

6. 60a fluoro 9a halo-1lfl,17u,21-trihydroxy-l6,B-methyl-4-pregnene-3,ZO-dione 21-acylate wherein the acyl radical is thatof a hydrocarbon carboxylic acid contain ing from one to twelve carbonatoms, inclusive, and wherein the halogen has an atomic weight from 19to 36, inclusive.

7. 60:,9oc difluoro 11B,17a,21-trihydroXy-16,B-methyl-4-pregnene-3,20-dione 2l-acetate.

8. 60,9a difluoro '115,1704,21-trihydroxy 16fl-methyl-4-pregnene-3,20-dione.

9. 6oz fluoro 165 methyl 17a,21dihydroxy-l,4- pregnadiene-3,l1,20-trione2l-acetate.

10. 60c fluoro 16,8 methyl 17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione.

11. 6oz fluoro 11[3,17a,2l-trihydroxy-l6fl-methyl-1,4-pregnadiene-3,20-dione.

12. 60 fluoro 11fi,17a,21 trihydroxy 16,8-methyl- 1,4pregnadiene-3,20-dione ZI-acylate wherein the acyl radical is that of ahydrocarbon carboxylic acid containing from one to twelve carbon atoms,inclusive.

13. 60c fluoro 11fi,17a,21 trihydroxy 16,8-methyl-1,4-pregnadiene-3,20-dione 21-acetate.

14. 60c fluoro c halo 11,3,17a,2ltrihydroxyl6,6-methyl-1,4-pregnadiene-3,20-dione 21-acetate wherein theacyl radical is that of a hydrocarbon carboxylic acid containing fromone to twelve carbon atoms, inclusive, and wherein the halogen has anatomic Weight from 19 to 36, inclusive.

15. 6a,9a difiuoro 11B,17a,21 trihydroxymethyl-l,4-pregnadiene-3,20-dione 21-acetate.

16. 60:,9a difiuoro l1/3,17ix,2l trihydroxy-16(3-methyl-1,4-pregnadiene-3 ,20-dione.

17. 611,21 difluoro 11,8,170: dihydroXy-16fl-methyl-1,4-pregnadiene-3,20-dione.

18. 6a,9a,21 trifluoro-l16,17a-dihydroxyl-l6B-methyl-1,4-pregnadiene-3,20-dione.

19. 604,21 difluoro 1l 8,17a dihydroxy-16fl-methyl-4-pregnene-3,20-dione.

20. 6a,9ot,21 trifluoro-l1,8,17a-dihydroxy-16fi-rnethyl-4-pregnene-3,20-dione.

21. 6a-fluoro-1113,17a-dihydroxy-16p-methy1 4 pregnene-3,20-dione.

22. 601,95; difiuoro 11p,17a-dihydroxy-165-methyl-4-pregnene-3,20-dione.

23. 6a fluoro 115,170; dihydroXy-16p-methyl-L4- pregnadiene-3,20-dione.

24. 600,90: difluoro 11,8,17a-dihydr0xy-16fl-methyl-1,4-pregnadiene-3,20-dione.

25. 6u-fluoro-165-methyl steroid compound of the formula:

wherein R is a member of the group consisting of hy-

